DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
CARDIOVASCULAR AND RENAL DRUGS
P A R T I C I P A N T S
Dornette Spell-LeSane, M.H.A., NP-C, Executive
Jeffrey S. Borer, M.D., Acting Chairman
Steve Nissen, M.D.
Alan T. Hirsch, M.D.
Thomas Fleming, Ph.D.
Maria H. Sjogren, M.D.
Jonathan Sackner-Bernstein, M.D.
John R. Teerlink M.D.
Susanna L. Cunningham, Ph.D.
William R. Hiatt, M.D.
Beverly H. Lorell, M.D.
Thomas Pickering, M.D.
Ronald Portman, M.D.
Paul Watkins, M.D., Ph.D.
Jose Vega, M.D.
Dr. Mark Avigan
Dr. Florence Houn
Dr. Joyce Korvick
C O N T E N T S
AGENDA ITEM PAGE
Call to Order and Introductions - Jeffrey S. Borer,
M.D., Acting Chair 5
Conflict of Interest Statement - Dornette
Spell-LeSane, NP-C, Executive Secretary 8
Welcome and Comments - Norman Stockbridge, M.D.,
Acting Director, Division of Cardiovascular and
Renal Drug Products, FDA 13
Introduction - Hamish Cameron, M.D., Vice
President, Exanta 15
Clinical Pharmacology - Troy Sarich, Ph.D.,
Director, Clinical Pharmacology 24
Efficacy - Jay Horrow, M.D., Senior Director,
Clinical Development 43
Safety - Sunita Sheth, M.D., Senior Director,
Clinical Development 97
Benefit and Risk Anticoagulation - Jonathan L.
Risk/Benefit Assessment - Ruyi He, M.D., Medical
Officer, Division of Gastrointestinal and
Coagulation Drug Products 172
Risk Management of Hepatotoxic Drugs - Kate
Gelperin, M.D., M.P.H., Medical Epidemiologist,
Division of Drug Risk Evaluation 282
Drug-Induced Liver Toxicity - Paul Watkins, M.D.,
Verne S. Caviness Distinguished Professor of
Medicine, Director, General Clinical Research
Medical Center 301
C O N T E N T S (Continued)
AGENDA ITEM PAGE
Questions from the Committee --
Open Public Hearing 184
Charge to the Committee - Joyce Korvick, M.D.,
M.P.H., Acting Division Director, Division of
Gastrointestinal and Coagulation Drug Products, FDA 318
Committee Discussion 319
Committee Questions/Summary 320
P R O C E E D I N G S
DR. BORER: It's and I'm going to
call the meeting to order. This is the Cardiovascular and
Renal Drugs Advisory Committee
meeting, and we will discuss New Drug Application
(NDA) 21-686, proposed trade name Exanta
(ximelagatran) by AstraZeneca, for the proposed
indication of the prevention of venous thromboembolism in
patients undergoing knee replacement
surgery, the prevention of stroke and other
thromboembolic complications associated with atrial
fibrillation, and the long-term secondary
prevention of venous thromboembolic events after
standard treatment following an episode of acute
venous thromboembolic event.
We'll begin by introducing everybody at
the table. In this meeting, the Cardio/Renal
Committee actually is advising the GI Division as
well as Cardio/Renal, in fact, primarily the GI
Division, so we have more people at the table than
we sometimes do. Maybe we can each say our name
and what we're doing here, and we'll
start with Dr.
Vega on the far side.
DR. VEGA: I'm Jose Vega. I'm the
industry representative on the committee, and I'm
DR. PICKERING: Tom Pickering from
DR. PORTMAN: Ron Portman from the
DR. HIATT: Bill Hiatt, University of
DR. LORELL: Bev Lorell, Harvard Medical
School, and also Guidant Corporation.
DR. SACKNER-BERNSTEIN: Jonathan
DR. CUNNINGHAM: Susanna Cunningham. I am
the consumer representative on the committee, and
I'm from the
DR. NISSEN: I'm Steve Nissen. I'm a
cardiologist at the Cleveland Clinic.
DR. WATKINS: Paul Watkins. I'm a
hepatology consultant from
DR. BORER: Jeff Borer, cardiologist,
MS. SPELL-LeSANE: Dornette Spell-LeSane,
Executive Secretary for the committee.
DR. TEERLINK: John Teerlink, University
of California-San Francisco, and
DR. FLEMING: Tom Fleming, University of
DR. HIRSCH: Alan Hirsch, cardiologist and
vascular medicine specialist at the University of
DR. AVIGAN: Mark Avigan, Office of Drug
Safety at the FDA.
DR. STOCKBRIDGE: I'm Norman Stockbridge,
the Acting Director of the Division of Cardio/Renal
Drug Products at FDA.
DR. HOUN: I'm Florence Houn. I'm the
Office Director for Drug Evaluation III.
DR. KORVICK: Joyce Korvick, Acting
Director, Division of Gastrointestinal
DR. ROBIE-SUH: Kathy Robie-Suh, Acting
Deputy Director, Division of Gastrointestinal and
Coagulation Drug Products.
DR. BORER: Thank you very much.
We have many people at the table. I'm
going to remind everyone that when you speak, you
should press the button on your microphone, and
when you're done, turn it off, please, unless you
want to say something because that's the only way
I'm going to know that you want to if you press the
button and I see the light.
We'll go on to the conflict of interest
statement. Dornette Spell-LeSane, the Executive
Secretary of the Cardio/Renal Drug Advisory
Committee, will present the conflict of interest.
MS. SPELL-LeSANE: Good morning. The
following announcement addresses the issue of
conflict of interest and is made part of the record
to preclude even the appearance of such at this
meeting. Based on the submitted agenda and all
financial interests reported by the committee
participants, it has been determined that all
interests in firms regulated by the Center for Drug
Evaluation and Research present no potential for an
appearance of a conflict of interest at this
meeting, with the following exceptions:
In accordance with 18 U.S.C. Section
208(b)(3), full waivers have been granted to the
following participants. Please note that all of
the consulting and speaking activities waived are
unrelated to Exanta and its competing products:
Dr. William Hiatt for consulting for two
competitors for which he receives less than $10,001
per year per firm;
Dr. Thomas Pickering for serving on a
competitor's advisory board for which he receives
less than $10,001 per year;
Dr. Ronald Portman for consulting for a
competitor for which he receives less than $10,001
Dr. Thomas Fleming for consulting for four
competitors, he receives less than $10,001 per year
Dr. Sackner-Bernstein for consulting for
the sponsor and a competing firm, he receives less
than $10,001 per year per firm. Also, for his
Speaker Bureau activities for a competitor, he
receives less than $10,001 to $50,000 per year;
Dr. Jeffrey Borer for serving on a
steering committee for a competitor, he receives
less than $10,001 per year;
Dr. Alan Hirsch for lecturing for the
sponsor, for which he receives less than $5,001 per
year. For lecturing for three competing firms, he
receives less than $5,001 per year for serving on
two Speaker Bureaus, and from $5,001 to $10,001 for
one Speakers Bureau. Two consulting agreements for
two competing firms, he receives less than $10,001
per year for one consulting, and from $10,001 to
$50,000 per year for the other.
In accordance with 18 U.S.C. 208(b)(3), a
limited waiver has been granted to Dr. Paul Watkins
for serving on two advisory boards for a competing
firm. He receives less than $10,001 per year for
one and greater than $50,000 per year for
other. Under the terms of this limited waiver, Dr.
Watkins will be permitted to participate in the
committee's discussion of Exanta. He is, however,
excluded from voting.
Lastly, in accordance with 18 U.S.C.
Section 208(b)(1), full waivers have been granted
to the following participants for interests
unrelated to Exanta and its competing products:
Dr. John Teerlink for speaking for two
competitors, he receives less than $10,001 per year
from one, and from $10,001 to $50,000 per year from
the other. Also, for his consulting for a
competitor for which he receives between $10,000 to
$50,000 per year;
Dr. Maria Sjogren for consulting for a
competitor for which she receives less than $10,001
A copy of the waiver statement may be
obtained by submitting a written request to the
agency's Freedom of Information Office, Room 12A-30
discussions involve any other products or
already on the agenda for which FDA participants
have a financial interest, the participants are
aware of the need to exclude themselves from such
involvement, and their exclusion will be noted for
We would also like to note that Dr. Jose
Vega has been invited to participate as an industry
representative acting on behalf of regulated
industry. Dr. Vega is employed by Amgen.
With respect to all other participants, we
ask in the interest of fairness that they address
any current or previous financial involvement with
any firm whose products they may wish to comment
DR. BORER: Thank you very much, Dornette.
That was about the longest conflict of interest
statement that I can remember.
But we still are five minutes ahead,
Norman Stockbridge, the Acting Director of the
Division of Cardiovascular and Renal Drug
DR. STOCKBRIDGE: I'll see if I can keep
us on schedule. Good morning and welcome to what
promises to be an interesting meeting on behalf of
the Divisions of Cardio/Renal Drug Products and GI
and Coagulation Drug Products. I want to thank
members of the Cardio/Renal Advisory Committee,
consultants, and the sponsor for their
I do need to acknowledge retirement of
four members from the Advisory Committee: Alan
Hirsch is here today, a couple of chairs down to my
left; Steve Nissen is over at the middle of the
table there; Paul Armstrong would be here today
except that Homeland Security discovered that he's
DR. STOCKBRIDGE: And, finally, there is
our Chairman, Dr. Jeff Borer. Dr. Borer's service
to the committee began in 1977, an era in which
members still sported powdered wigs.
DR. STOCKBRIDGE: I can't quite tell from
the records where he cast his first vote, but in
that year, the committee heard arguments on
potassium and atropine.
As tokens of our appreciation, Ms.
Spell-LeSane has for each of you some actual
certificates signed by our Acting Commissioner and
some virtual plaques that look just like this one.
So on behalf of Cardio/Renal, the Food and Drug
Administration, and a grateful nation, thanks to
DR. NISSEN: Norman, I'm not from Canada,
but I'm from Cleveland, and it's really close to
Canada. Will you please not tell Homeland Security
DR. BORER: Thank you very much, Norman,
and thank you for staying way on time because we
are now 17 minutes ahead of schedule, which is
good. The sponsor has a 90-minute presentation.
We'll try to allow you to move along as well as we
can, but undoubtedly there will be some clarification
questions. We ought to try to hold the
questions that we ask to clarification issues
during the presentation, if we can, and we can get
into the meat of the substantive discussion
The presentation will be introduced by Dr.
Cameron, the Vice President of Exanta.
DR. CAMERON: Thank you, Mr. Chairman,
members of the committee, ladies and gentlemen,
good morning. I'm Dr. Hamish Cameron, the Vice
President of Exanta at AstraZeneca, and with my
colleagues we're pleased to present ximelagatran, a
new oral anticoagulant.
After a 20-year journey to discover and
develop this new medicine and half a century
without significant innovation in this area of
therapeutics, we believe ximelagatran, the first
oral treatment in the new drug class direct
thrombin inhibitors is a real advance in oral
Ximelagatran has a mechanism of action
that's quite different from the vitamin K
antagonists like warfarin and can provide
oral alternative to warfarin, today's only option
for long-term anticoagulation.
Anticoagulation is the major approach to
both the prevention and treatment of thromboembolic
disease, a disease that's the final common pathway
for many life-threatening conditions, like stroke,
myocardial infarction, and pulmonary embolism. And
it's the commonest cause of death and disability in
At the outset we must ask: Given the
widespread availability of the vitamin K
antagonists like warfarin, why is there a need for
a new oral anticoagulant? Warfarin is a highly
efficacious anticoagulant and one of the top ten
most prescribed drugs, used in nearly every medical
specialty by 3 million patients in the U.S.
involving 32 million prescriptions every year. But
it's been in the top five, sometimes number one, in
the lists of drugs associated with significant
interactions, medication errors, serious bleeding,
and hospital admissions.
Warfarin's profile of
kinetics and dynamics; food, alcohol, and multiple
drug interactions; together with its acknowledged
narrow therapeutic index--too little warfarin, and
there's the risk of residual clotting; too much,
and the risk of bleeding--all these drive the need
for a lifetime of INR coagulation monitoring and
never-ending individual dose titration.
To put it simply, you don't get the
benefit of warfarin from just taking the tablet.
Its overall effectiveness is highly dependent on
how it's managed. And it's this fact that frames
the innovation of ximelagatran.
Many patients and doctors fear the risk of
bleeding that comes with unpredictable anticoagulation.
This fear tends to result in
under-treatment, quite paradoxical in high-risk
elderly patients, or in about half the overall
patients eligible for warfarin, little or no
treatment at all.
We started a discovery program targeting
thrombin in 1985. We sought to develop a new oral
anticoagulant, an alternative to
warfarin, with a
profile that would allow fixed dosing without
coagulation monitoring, further supported by a low
potential for food and drug interactions.
We looked for a rapid onset and offset of
action to simplify turning anticoagulation on and
off, which is one of the challenging aspects of
warfarin treatment. And all this had to be
achieved with an acceptable bleeding profile.
Today, we believe these objectives have
been met by the Ximelagatran Development Program,
involving 82 clinical studies and enrolling over
30,000 subjects. More than 17,000 people received
ximelagatran with 3,500 patients dosed for over a
year. And our longest patient exposure has now
reached five years.
Here are the three proposed indications in
the current NDA, spanning exposures from days to
several years. The first is the long-term
secondary prevention of venous thromboembolism,
VTE, after standard treatment for an acute episode.
Treatment of acute VTE involved six months of
anticoagulation with warfarin, but at the
this development in 1999, it was unknown whether
longer treatment would be beneficial. And so a
placebo-controlled study, THRIVE III, was
conducted. As you'll see, this study demonstrated
a highly significant reduction of VTE during
longer-term prophylactic treatment. And as a
placebo-controlled study, it provides the strongest
evidence of ximelagatran's antithrombotic efficacy.
The second indication is the prevention of
VTE after knee replacement surgery. Patients
without anticoagulant prophylaxis run a high risk
of DVT and pulmonary embolism, and in the U.S.,
warfarin is the most widely used drug, started late
on the day of surgery to reduce this risk. In two
warfarin controlled studies, EXULT A and EXULT B,
we've shown a significant reduction of VTE risk for
ximelagatran compared with warfarin.
The third indication is the prevention of
stroke and other thromboembolic complications
associated with atrial fibrillation. Here with the
large SPORTIF III and V trials, we've shown the
efficacy of ximelagatran to be comparable
Across these pivotal, mainly
outcomes-based studies involving independent
endpoint adjudication, we've demonstrated
ximelagatran's antithrombotic efficacy and recorded
a favorable leading profile, equivalent to and in
some cases better than the comparator. We detected
a signal of raised hepatic enzymes with chronic
treatment, and so we've conducted a very detailed
analysis, consulted with experts, and believe the
risk can be adequately managed.
I should highlight that in your briefing
packs and our safety presentation, we've included
data from two other large studies in other
indications, not for consideration today, but which
contribute nearly 4,000 patients. The THRIVE
treatment study is the first pivotal study looking
at initial VTE treatment, and the second study is
soon to start, while the ESTEEM trial is a Phase II
dose guiding study in the post-acute coronary
These data enrich the overall
assessment, including patients from very different
clinical settings and a wide range of characteristics, and
we're going to review all the key
data in the presentations that follow.
We believe ximelagatran with its
predictable anticoagulant effects and favorable
bleeding profile has a positive benefit/risk in the
proposed indications, provided it's used properly.
And part of that proper use is the introduction of
an appropriate risk management program directed
towards the hepatic risk.
We made an initial proposal with our
submission which had been developed with extensive
external consultation and field testing, but we
fully recognize, following the deliberations of
this committee and further discussions with FDA,
the program will need to be developed and
strengthened further before an approach can be
finalized in the best interests of patients. We
are committed to working with FDA to achieve the
most appropriate risk management program to ensure
the safe use of ximelagatran because
is, has been, and always will be AstraZeneca's top
priority when we introduce new medicines into
Since 1998, we've met repeatedly with FDA
throughout ximelagatran's development--in end of
Phase II meetings, a pre-NDA interaction, and
there's a meeting coming up to discuss the nature
and extent of the risk management program. The NDA
was submitted in December 2003.
I should add that all the same data are
now being reviewed in Europe by the French agency
before a mutual recognition procedure. But there's
one difference worth noting. Given the quite
different clinical practice regarding anticoagulant
prophylaxis in orthopedic surgery, separate
developments were conducted in the U.S. and Europe.
The European program, reflecting local practice and
starting treatment much closer to the time of
operation, was the subject of a separate earlier
regulatory submission and completed the mutual
recognition procedure in May this year. And the
first orthopedic launch was in Germany in
Now, you have the data on this program in
your briefing packs, but with the significant
timing, comparator, and formulation differences,
our presentations today will largely focus on the
data directly relevant to the NDA orthopedic
Here's the agenda for our session. Dr.
Troy Sarich will review clinical pharmacology; Dr.
Jay Horrow, efficacy; and Dr. Sunita Sheth, safety;
allowing an overall evaluation of ximelagatran in
the three requested indications. Dr. Jonathan
Halperin from Mount Sinai Medical Center will then
give his views on the benefit/risk of ximelagatran
in clinical practice. And throughout our
presentations, we hope to cover for you all the
specific comments raised by the agency in their
In addition to Dr. Halperin, we're also
joined by other consultants: Dr. Gerald Faich, Dr.
Lloyd Fisher, Dr. Peter Kowey, and Dr. James Lewis.
In summary, then, ximelagatran is a new
oral anticoagulant that provides the
alternative to warfarin after 50 years. We believe
a total review of the available clinical data
supports a positive benefit/risk in each of the
proposed indications. Ximelagatran can enhance
health care delivery in America and throughout the
world to help prevent a range of debilitating and
life-threatening thromboembolic diseases.
Thank you. Now I'd like to introduce Dr.
Troy Sarich for clinical pharmacology.
DR. SARICH: Good morning. I'm Dr. Troy
Sarich, Director of Clinical Pharmacology at
AstraZeneca. I'll now present an overview of the
clinical pharmacology of ximelagatran in which we
have performed both the traditional clinical
pharmacology studies and population pharmacokinetic
Ximelagatran is an oral direct thrombin
inhibitor. It's rapidly bioconverted to the active
form, melagatran. The bioconversion, which is
Cytochrome P-450 independent, involves both
de-esterification and a reduction that occurs
throughout the body.
The exposure to melagatran is linear
across a dose range from 5 to 98 milligrams
ximelagatran. The pharmacokinetics are predictable
over time with repeated dosing, and the elimination
half-life of melagatran is approximately 4 to 5
hours in patients. Once formed, melagatran is
primarily eliminated from plasma by a glomerular
Thrombin is a key enzyme in the
coagulation cascade. It converts fibrinogen to
fibrin, activates platelets, and induces its own
generation. Melagatran directly inhibits thrombin
as a classic competitive and reversible-binding
enzyme inhibitor. There's a direct relationship
between the pharmacokinetics and pharmacodynamics
of ximelagatran. Its active when present in
plasma, and once eliminated from plasma, its effect
Preclinical investigations indicated an
antithrombotic effect of melagatran at approximately 0.05
micromolar, with increasing effect up
to approximately 0.5 micromolar.
In humans, ximelagatran prolongs clotting
time assays. The thrombin time assay shown here
was prolonged in a linear manner at concentrations
as low as 0.05 micromolar. In addition, melagatran
prolongs in a concentration-dependent manner the
activated partial thromboplastin time, although it
is less sensitive.
Additional investigations using
pharmacodynamic models in humans demonstrated
evidence for inhibition of thrombin generation
indicated by concentration-dependent reduction and
thrombin-antithrombin complex levels and platelet
activation indicated by concentration-dependent
reduction in beta thromboglobulin levels at
melagatran concentrations at or near 0.05
micromolar. All together, it was clear from these
data that direct inhibition of thrombin by
melagatran resulted in the intended anticoagulant
activity in humans.
After oral administration, the inactive
pro drug ximelagatran is rapidly eliminated from
plasma as it is biotransformed to
in blue, with peak melagatran concentrations
occurring approximately 2 to 3 hours post-dosing.
Melagatran plasma concentrations greater than 0.05
micromolar are achieved early after oral ximelagatran,
indicating a rapid onset of action which
simplifies the initiation of oral anticoagulation.
Concentrations remain above 0.05 micromolar
throughout the dosing interval, supporting a
twice-daily dosing regimen.
And as shown here, the rapid onset of
action of oral ximelagatran is not altered when
co-administered with food. Although there's an
approximately one-hour delay in the time to C-max,
there is no effect on the AUC or Cmax of
Warfarin's well-recognized drug
interaction profile is largely related to its
metabolism by the Cytochrome P-450 system and its
high plasma protein binding. Ximelagatran is not
metabolized by and does not inhibit the major
Cytochrome P-450 enzymes listed here. It also has
low plasma protein binding, and along
majority of melagatran eliminated from plasma by
glomerular filtration, this leads to an inherently
low potential for drug interactions.
Our investigations have identified
pharmacokinetic interactions with erythromycin and
azithromycin. Erythromycin results in an
80-percent or less than twofold increase in
melagatran plasma levels, with a smaller, 40- to
60-percent increase with azithromycin.
These changes are within the overall range
of melagatran exposures in patients, and as
outlined in detail in your briefing document,
investigation into the potential impact of this
pharmacokinetic interaction found no signal for
increases bleeding events or increased ALT
elevations in the approximately 230 patients
receiving ximelagatran and macrolide antibiotics in
the long-term studies. These data do not suggest
an important clinical impact of these
We have conducted many other interaction
studies where we've found no significant
pharmacokinetic interactions. As shown by the mean
melagatran AUC ration and the 90-percent confidence
interval within or slightly outside the 0.8 to 1.25
no interaction interval. The drugs investigated
include alcohol, common cardiovascular medications,
an NSAID, a sedative, and several antibiotics.
These results are consistent with population
pharmacokinetic analyses indicating a lack of
interaction with commonly used comedications in the
patient studies. Taken together, these data
suggest that ximelagatran has a low potential for
Melagatran is primarily renally eliminated
from plasma, and so we've carefully investigated
the impact of renal function on the pharmacokinetics of
ximelagatran. In the three patient
populations under consideration today, melagatran
exposure increases as calculated creatinine
clearance decreases. For this reason, severe renal
impairment, a calculated creatinine clearance less
than 30 mLs per minute, was an exclusion criteria
for our clinical studies, and we're
investigating an alternative dosing strategy in
It's notable that we've gathered
considerable experience with ximelagatran in
patients with mild to moderate renal impairment as
approximately 45 percent of the Phase III patient
population had a calculated creatinine clearance
between 30 and 80 mLs per minute. The median
exposures in these patients are about 1.5 to 2.5
times higher, respectively, than patients with
normal renal function, but there's considerable
overlap in melagatran exposure between groups,
suggesting dose adjustment was not necessary.
We've also studied the potential effects
on the pharmacokinetics of ximelagatran within
other special populations, and other than
differences in renal function between groups, we
have not identified other important effects of age,
gender, race, obesity--as measured using body mass
index--or body weight on the pharmacokinetics of
The agency has suggested there
should be a
dose adjustment for ximelagatran in patients with
renal impairment given the higher levels of
melagatran in these patients. But I'd like to show
you why a fixed dose, as used in our clinical
studies, is appropriate across the patient
We do agree with the agency's assessment
that there's no need for dose adjustment in
orthopedic surgery patients and that there was no
increased bleeding related to melagatran exposure
in VTE secondary prevention patients. We do
acknowledge an association between increasing
melagatran exposure and increasing incidence of
major bleeding in atrial fibrillation patients.
But this relationship appears confounded by the
correlation between melagatran exposure and the
age-related decrease in calculated creatinine
Shown here from the SPORTIF trials is the
relationship between calculated creatinine
clearance and major bleeding. As you can see,
major bleeding increased with declining
function whether patients received ximelagatran or
INR-controlled warfarin. This suggests the
increase in melagatran concentrations in patients
with renal impairment is not associated with
increased bleeding versus INR-controlled warfarin.
It's also important to note that stroke
risk increased with decreasing calculated
creatinine clearance, and the vast majority of
these strokes were ischemic. So there's a
possibility that a dose reduction in renally
impaired patients intended to decrease bleeding may
increase the risk of stroke in those patients at
We should also consider the hepatic
findings, as will be presented by Dr. Sheth, and we
have examined the possible relationship between
melagatran exposure and ALT elevations. As pointed
out in our briefing document, we have observed an
association between increasing melagatran exposure
and increasing ALT elevations greater than 3 times
upper limit of normal, but this relationship is
very weak. And as shown here, the relationship
between melagatran AUC and peak ALT elevation in
individual patients, while statistically
significant, does not suggest a clear relationship
between melagatran exposure and ALT elevations.
In addition, we agree with the agency's
conclusion that, aside from the ALT elevations
noted with ximelagatran, there is no difference in
the overall adverse event profile between
ximelagatran and comparators in the long-term
dosing study pool.
Factoring in the occurrence of major
bleeding, stroke and systemic embolic events, ALT
elevations, and the overall adverse event profile,
the observation of increased plasma melagatran
concentrations in renal impairment does not appear
to justify a dose reduction in these patients. We
believe our data support a fixed dose of
ximelagatran in the patient populations studied.
Now I'd like to show the steady-state
plasma concentrations of melagatran in atrial
fibrillation patients receiving a fixed dose of 36
milligrams ximelagatran twice daily. There are
four key points here.
Plasma concentrations fluctuate during the
dosing interval, remaining largely above 0.05
micromolar and infrequently exceeding 1 micromolar.
Mean trough melagatran concentrations
after 36 milligrams are approximately 0.2
micromolar. So should a patient miss a dose of
ximelagatran, the 4- to 5-hour half-life of
melagatran means that low but pharmacologically
active concentrations remain for up to 24 hours
post-dosing. And the effect of melagatran is gone
once it is cleared from plasma by the kidneys.
This emphasizes the importance of
maintaining good diuresis in the management of
bleeding. And while there is no specific antidote,
if needed, melagatran can be dialyzed.
And, lastly, the APTT is prolonged in
patients and may help identify a residual
A critical aspect of oral anticoagulation
is maintenance of a stable effect over time, and we
have confirmed the long-term stability of
ximelagatran. Shown in yellow are the plasma
concentrations of melagatran in atrial fibrillation
patients in the Phase II study, SPORTIF II. We
remeasured plasma melagatran concentrations in a
subset of those same patients between 13 to 16
months later in SPORTIF IV, a long-term
continuation study of SPORTIF II.
The mean plasma concentrations of
melagatran are completely overlapping, and the
variability in exposure within individual patients
was low, with a coefficient of variation of 25
percent, indicating that oral ximelagatran results
in stable and reproducible plasma concentrations of
melagatran with long-term repeated dosing. This
stability enabled us to conduct our clinical
studies using a fixed dose without coagulation
So we can conclude from this extensive
clinical pharmacology program pharmacologically
active concentrations of melagatran are rapidly
achieved and maintained in a broad range of
There is also no effect of food or
alcohol and a low potential for drug interactions.
The key attributes of ximelagatran are,
therefore, its oral availability, rapid onset of
action, low potential for drug interactions, and
use at a fixed dose without coagulation monitoring.
Now I'd like to introduce Dr. Jay Horrow,
who will provide to you an evaluation of the
efficacy of ximelagatran demonstrated in Phase III
DR. BORER: We'll just stop for one moment
to make sure there are no issues that need to be
clarified. The relation of renal function to
melagatran exposure undoubtedly is going to be
discussed to a greater extent later, but I think we
should hold that until we hear from the FDA
presentations, and then we can talk about that.
But if there are any issues that need to be
clarified regarding the pharmacology, we should do
DR. NISSEN: Two very brief questions. Is
anything known about the mechanism of
interaction? Have you explored that at all?
DR. SARICH: Yes. We were slightly
surprised to find that interaction since we don't
interact with the P-450 system. It appears that
the interaction involves transport proteins of some
kind, and we've looked at a range of different
compounds that we've investigated, and it at this
point appears isolated to the macrolide antibiotics
DR. NISSEN: And the second question is:
You showed the coagulation effect during therapy,
and I wondered if you have additional data on what
happens in, let's say, the first 72 to 96 hours
after terminating therapy. Is there evidence of a
DR. SARICH: We have not observed that
pharmacologically, as far as coagulation time
DR. NISSEN: Okay. But that has been
DR. SARICH: We've followed out to 24
hours after single-dose administration
and not seen
DR. NISSEN: But not longer than 24 hours?
DR. SARICH: Not that I can recall.
DR. BORER: John?
DR. TEERLINK: The other question I have
is: In terms of the relationship between the
melagatran AUC versus the peak ALT elevations, how
was the melagatran AUC derived?
DR. SARICH: Yes, these were derived using
a population pharmacokinetic model. So the
patients that received ximelagatran in the Phase
III clinical studies had plasma samples collected.
Over 80 percent of the Phase III patient
population--in the long-term population had a
plasma sample collected. Using a pharmacokinetic
model that was developed by the team, we were able
to estimate the exposure to melagatran in those
DR. BORER: Ron Portman?
DR. PORTMAN: Noting differences in the
chronopharmacology of drugs, were the curves you
showed similar for both the morning and evening
DR. SARICH: Are you speaking about the
coagulation time assay--
DR. PORTMAN: No. I was talking about the
DR. SARICH: Pharmacokinetics?
DR. PORTMAN: Right, pharmacokinetics.
DR. SARICH: Yes, they are consistent
under administration during the day or overnight.
DR. BORER: Jonathan, go ahead.
DR. SACKNER-BERNSTEIN: In the analysis
that you showed the stability of the concentrations
of the drug over time from the SPORTIF II and
SPORTIF IV population, did you perform that
analysis restricting to patients who had samples at
both times? Because the analysis you showed had a
larger population at baseline compared to a subset
DR. SARICH: Right. We've done it both
ways. The figure actually represents the larger
number in the SPORTIF II study and a smaller number
in SPORTIF IV. The intra-subject variability I
noted was only the subjects that had sampling at
both time occasions.
DR. BORER: Alan?
DR. HIRSCH: In the PK and AUC curves that
you've generated, were there any changes or
differences noted based on ethnicity, geographic
sampling of a population, or gender?
DR. SARICH: Are you asking pharmacokinetic--
DR. HIRSCH: Yes, PPK differences between
DR. SARICH: The main factor we've
observed between any subgroups has been differences
in renal function, calculated creatinine clearance.
We have not observed any significant effects of
other demographic parameters, age, gender, race,
BMI, body weight. It appears that exposure--the
most influential demographic factor is calculated
DR. BORER: Susanna?
DR. CUNNINGHAM: Did you have a sufficient
African American population to actually
anything about what the African American area of
the curve might be or handling of the drug?
DR. SARICH: We have performed pharmacokinetic
studies in that population. I should say
both--I'll show you some data here from a small
study. It's not African Americans per se, but it
was a study in Europe, in Paris, in fact, where we
had 12 blacks, 12 Asians, and 12 Caucasians, and
found no real differences between these groups.
If we looked at the entire patient
population, we can see here--if we look at--you can
see the Caucasian population here. There's over
6,000 patients. The blacks where we had
appropriate pharmacokinetic information, were 115,
as well as Asians, and the category of other, and
no differences between these populations.
DR. BORER: Tom?
DR. PICKERING: Do you have any data on
interaction with aspirin?
DR. SARICH: Yes, we have performed
actually two studies with aspirin. There's no
pharmacokinetic interaction with
aspirin. We see
an additive effect on the capillary bleeding time,
which is somewhat expected.
DR. BORER: Beverly?
DR. LORELL: Yes, with regard to body
size, you commented on and emphasized obesity.
What about the other end of the scale, very small
body size? Sometimes an issue in elderly women who
might be candidates for several of these
DR. SARICH: We have less data in very
small individuals, but what we know about that
population is that it's primarily their calculated
creatinine clearance that influences their
DR. BORER: Jonathan?
DR. SACKNER-BERNSTEIN: I know we're going
to get back to the renal function question, but
there was one set of slides you showed where you
tried to give us some reassurance about the
relationship between bleeding and renal function.
And you showed the risk of bleeding as calculated
creatinine clearance reached the low end
I wonder if you performed any sort of
retrospective power calculation on your ability to
detect a difference in risk, in particular in the
patients who we may be likely to see treated with
this drug in clinical practice, those over 70, over
75, where calculated creatinine clearances often
are in the 40s. So do you have an analysis there
between 30 and 50 with conditional power to
actually detect a difference in bleeding risk
DR. SARICH: I think we could probably
best address that after the presentations. We do
have data there, and rather than getting into that
discussion, if the Chair would agree, we could
address that, bring an answer to you for that.
DR. BORER: Is that okay, Jonathan?
DR. SACKNER-BERNSTEIN: Yes.
DR. BORER: Okay. Thank you.
T1B DR. HORROW: Ladies and
gentlemen, I'm Dr. Jay Horrow from AstraZeneca. We
will now present Phase III data
ximelagatran is an effective oral anticoagulant.
In the first indication, long-term
secondary prevention of venous thromboembolism, we
will show ximelagatran superior to placebo. In the
second indication, prevention of VTE after total
knee replacement, ximelagatran was superior to
well-controlled anticoagulation with warfarin. And
in the chronic prevention of stroke, ximelagatran
was noninferior to warfarin.
These indications represent a broad range
of patient populations. We'll begin with the first
one: secondary prevention of VTE.
Evidence has been accumulating that
patients with acute VTE benefit from prolonged
anticoagulation after acute treatment. The THRIVE
III trial comparing ximelagatran to placebo
contributes to this growing body of evidence.
Randomized patients had an acute symptomatic VTE
objectively confirmed and had completed 6 months of
treatment without VTE recurrence, also objectively
documented at randomization. Anticoagulation was
desirable but not essential for these
that is, they had idiopathic VTE or probable
hypercoagulable conditions. Health status had to
be compatible with survival for an additional 18
In THRIVE III, 1,223 patients receives in
double-blind fashion either oral ximelagatran 24
milligrams twice daily or placebo for up to 18
months. Selection of 24 milligrams for this trial
came from a consideration of preclinical data and
data from Phase II trials in the orthopedic surgery
indication. These PK data from a Phase II European
trial in patients undergoing hip or knee
replacement demonstrate that administration of 8
milligrams ximelagatran twice daily, the lowest
curve, achieves plasma melagatran concentrations of
about 0.05 micromolar. This is the level at which
anticoagulant activity with melagatran begins based
on the data previously shown by Dr. Sarich.
Progressively higher doses of oral
ximelagatran, 12, 18, and 24 milligrams, achieved
higher melagatran concentrations, more anticoagulant
activity, and more time above the 0.05
micromolar threshold for each dose.
Outcome data from that same orthopedic
surgery trial suggest that 24 milligrams is the
most promising dose for efficacy. The 24-milligram
dose also had a reassuring bleeding profile. We
chose 24 milligrams for THRIVE III with placebo
comparator without establishing dose-limiting
toxicity, in this case bleeding. The choice was an
informed judgment taking into consideration, first,
the need for efficacy demonstrated by the benefits
seen here in joint replacement, an intense
thrombotic stimulus; and, second, the need to avoid
excess bleeding because the standard of care is no
anticoagulant therapy at all.
The trial compared ximelagatran to placebo
in the rate of recurrence of symptomatic,
objectively confirmed VTE. VTE encompasses both
deep vein thrombosis, DVT, and pulmonary embolism,
PE, because PE originates from a thrombus in the
systemic venous circulation, whether overt or not.
The primary endpoint compared ximelagatran
to placebo using a time-to-event
recurrence of VTE required signs or symptoms of
VTE, that is, a clinical event, and subsequent
objective confirmation. A blinded independent
endpoint committee evaluated and adjudicated all
clinical endpoints, including major bleeding
The ximelagatran- and placebo-treated
cohorts displayed similar demographic profiles. As
indicated by creatinine clearance between 30 and
80, 23 percent had some degree of renal impairment.
The index VTE event was or included pulmonary
embolism for more than one-third of patients. This
Kaplan-Meier curve shows the cumulative incidence
of the primary outcome in the ximelagatran and
placebo groups, analyzed by intention to treat.
Seventy-one patients in the placebo group suffered
recurrent VTE, including 23 PEs, for a cumulative
rate of 12.6 percent, while only 12 patients in the
ximelagatran group had recurrent VTE, including
only two PEs, for a cumulative rate of 2.8 percent.
The 9.8-percent difference, significant at p less
than 0.0001 by log rang test indicates
that one VTE
recurrence is prevented by ximelagatran treatment
for up to 18 months to 10 patients. The associated
hazard ratio, 0.16, indicates a risk reduction of
84 percent by ximelagatran relative to placebo.
The composite endpoint of total VTE
included both DVT and PE. Benefit of ximelagatran
over placebo occurred for each component of this
composite endpoint--clinical DVT, clinical PE, and
The superiority of ximelagatran to placebo
is robust to multiple, prespecified sensitivity
analyses listed here. Each comparison demonstrated
a significance level less than 0.0001
Here we examine efficacy in subpopulations. Small
diamonds depict point estimates of
the odds ratios of ximelagatran to placebo, and
horizontal bars show their 95-percent confidence
intervals. Superiority of ximelagatran over
placebo remains in all subgroups strata of
In THRIVE III, the oral thrombin inhibitor
ximelagatran, 24 milligrams twice daily
for up to
18 months, effectively reduced the number of
recurrent VTE events following 6 months' treatment
of an acute VTE. The results are robust and
consistent across multiple endpoints and subgroups
and demonstrate a clinically relevant benefit.
The second indication under review today
is the prevention of VTE in patients undergoing
knee replacement surgery. Major joint replacement
surgery challenges any anticoagulant to prevent VTE
without counteracting surgical hemostasis. VTE
prevention contributes heavily to the benefit/risk
balance for joint replacement surgery.
The current options to reduce the
occurrence of VTE after total knee replacement
include the injectable agents low-molecular-weight
heparin and fondaparinux and oral warfarin. One
FDA comment regards the choice of warfarin as the
comparator for these trials.
We chose warfarin for several reasons:
First, it is the agent most commonly used
for this purpose in North America, and we
administered warfarin, as orthopedic
beginning the night of surgery.
Second, warfarin, like
low-molecular-weight heparin, is a Grade 1A
recommended therapy for this purpose, according to
current American College of Chest Physicians
Consensus Conference Guidelines.
And, third, warfarin is associated with
less bleeding than the injectable anticoagulants
and so is a more daunting comparator for
ximelagatran in terms of surgical hemostasis.
Two independent double-blind Phase III
trials--EXULT A and EXULT B--enrolled patients
undergoing primary elective total knee replacement.
EXULT A studied 24 and 36 milligrams ximelagatran
and warfarin. We had studied 24 milligrams in this
context previously and found protection similar to
but not better than warfarin at p equal 0.07. We
found that result surprising. Unsure whether or
not it was a Type II error, we designed EXULT A
with two ximelagatran arms: one using 24
milligrams and the other using 36 milligrams.
Warfarin and its paired placebo
typically practiced in the U.S., the evening of the
day of surgery while ximelagatran and its placebo
began early on the morning after the day of
surgery. Treatment continued for 7 to 12 days,
after which all patients underwent bilateral
Based on the results of EXULT A, EXULT B
studied only 36 milligrams ximelagatran and
warfarin. Warfarin was aggressively and
successfully dosed to drive the INR rapidly to its
target of 2.5, with an accepted range of 1.8 to
3.0. The primary outcome formed the composite of
distal and proximal DVT by venogram performed
between days 7 and 12, objectively confirmed
symptomatic DVT or pulmonary embolism up to 2 days
after venography, and all-cause mortality up to 2
days after venography. Both trials utilized the
same blinded independent committee for event
The treatment groups in the EXULT trials
were balanced and represented well the population
of patients in the United States
knee replacement. More than a third of the cohort
displayed some degree of renal impairment.
Here are the primary results for EXULT A
and EXULT B. In EXULT A, ximelagatran 36
milligrams, in yellow, showed superiority to
well-controlled anticoagulation with warfarin, in
gray, at p equals 0.003. EXULT B confirmed those
results, with p less than 10
-5. These results yield
relative risk reductions of 26 and 29 percent and
numbers needed to treat of 14 and 11, respectively.
In EXULT A, ximelagatran 24 milligrams, in
orange, and warfarin, in gray, did not differ, with
event rates of 24.9 and 27.6 percent, respectively.
That p value is 0.28.
The delay in anticoagulation with warfarin
administration suggests that it may act like a
placebo in EXULT. In fact, warfarin rates, in
gray, are the lowest ever obtained in knee
replacement clinical trials with warfarin, perhaps
because of the rapid achievement in EXULT of
therapeutic INRs. Placebo rates are historically
over 60 percent, and the mean INR in
EXULT was 2.4
on post-op day 3. The warfarin group provided a
formidable comparator for ximelagatran in the EXULT
Here we see results for the components of
the composite primary endpoint. As expected, the
majority of events occurred in the distal leg.
Rates for proximal DVT, for PE, and for death were
low in all treatment groups. Another point raised
by FDA is how clinically relevant distal DVT is as
a component of that endpoint. It's important to
note that 10 to 20 percent of distal thrombi extend
to become proximal thrombi, and either one can
cause pulmonary embolism, making all three
phenomena clinically relevant components of a
composite endpoint. In fact, proximal and distal
deep vein thrombosis detected by venography,
whether symptomatic or not, is a primary endpoint
historically accepted by the agency for VTE
prophylaxis registration trials.
This display of the primary outcome by
subgroup strata shows differences in event
incidences between the pooled
ximelagatran and pooled warfarin groups. These
results, with small numbers in just a few
subgroups, reveal no discrepancies in efficacy in
any particular subpopulation.
Oral ximelagatran, 36 milligrams, provided
superior protection against VTE and all-cause
mortality compared with well-controlled
anticoagulation with adjusted-dose warfarin, a
clinically relevant comparator. This superior
protection was consistent across multiple
subgroups. These data support the efficacy of
ximelagatran for the indication requested.
The third indication considered today is
the protection of patients from stroke and other
thromboembolic complications of atrial
fibrillation. We have demonstrated that
ximelagatran provides this protection, as well as
does warfarin, across a broadly based patient
Two independent pivotal trials--SPORTIF
III, dosed, open-label in 23 countries in Europe
and Asia, and SPORTIF V, conducted
North America--enrolled patients eligible for
warfarin therapy according to existing treatment
guidelines, that is, those with nonvalvular atrial
fibrillation with at least one additional risk
factor for stroke. Each SPORTIF trial by itself
studied more patients than all previous trials of
stroke prevention in atrial fibrillation combined.
Each trial compared 36 milligrams twice daily
ximelagatran to dose-adjusted warfarin in
preventing all strokes and systemic embolism, hard
clinical endpoints in an intention-to-treat
The choice of 36 milligrams came from
several considerations. There is no surrogate
marker for stroke and systemic embolism, and both
events are devastating. Thus, we performed a
dose-ranging study for safety and tolerability of
ximelagatran 20, 40, and 60 milligrams in SPORTIF
II, a 3-month Phase II atrial fibrillation study.
While the numbers were small in that study,
bleeding was most frequent with 60 milligrams and
also the warfarin comparator, and less
with 20 or 40 milligrams ximelagatran. We knew
that 24 milligrams was effective in the Phase II
European orthopedic surgery program and reasoned
that any downside impact of potential additional
strokes with 24 milligrams would be far worse than
the bleeding seen with 36 milligrams in this
nonsurgical context. Using this educated judgment,
we chose 36 milligrams in the Phase III atrial
Let's take a moment to consider the
open-label nature of the SPORTIF III trial. The
majority of prior stroke prevention trials in
atrial fibrillation also utilized an open-label
format based on the difficulty of managing
anticoagulation in blinded fashion. SPORTIF III
featured open-label dosing at sites, but also
centrally randomized allocation and two additional
levels of blinding: blinded local assessment of
primary endpoints by study-affiliated neurologists,
and blinded independent central committee
adjudication of all study endpoints. SPORTIF V
featured double-blind, double-dummy
for patients receiving ximelagatran and placebo
warfarin, sham INR values that mimicked those
obtained during warfarin therapy.
The established efficacy of warfarin
precluded a placebo comparison. Because warfarin
is so efficacious, it is reasonable to establish
ximelagatran efficacy in comparison to warfarin,
and we did so using a noninferiority design. In
consultation with an executive steering committee
and data safety monitoring board compose of leaders
of prior stroke prevention trials and a
statistician expert in noninferiority trials, we
prespecified a 2-percent per year absolute
noninferiority margin. The choice of this margin
has been questioned. The choice of 2 percent arose
partly from an expected 3.1 percent warfarin rate,
but more importantly, from consideration of the
clinically tolerable absolute difference in stroke
rates considering warfarin's overall clinical
profile. A similar consideration drove designers
of the SPAF III trial to power that trial to detect
a 2-percent per year event rate with
confidence bounds of 3 for a population at lower
risk of stroke. Even so, we prespecified a more
conservative 2-percent upper confidence limit. The
point estimate of the difference in event rates
needs to be much smaller than 2 percent for the
worst case, that is, the upper confidence limit, to
be less than 2.
The strength of the 2-percent per year
absolute margin resides in its clinical relevance,
its prespecification, and that it is conservative.
At screening, those patients already
taking oral anticoagulants interrupted that therapy
to decrease INR to 2 or less by the time of
randomization, at which time patients received
either warfarin or ximelagatran. Each trial
achieved a degree of warfarin control rarely found
in routine clinical practice. The warfarin-treated
groups constituted formidable comparators for
ximelagatran, particularly in SPORTIF V. Samsa and
colleagues found that most patients taking warfarin
spend more than half the time on treatment outside
the therapeutic range. In SPORTIF V, only 15
percent of patients did so.
The ximelagatran- and warfarin-treated
cohorts displayed nearly identical demographic
profiles in each independent Phase III trial, seen
here as pooled data. Patients reflected well the
elderly population of nonvalvular atrial
fibrillation patients requiring anticoagulation for
stroke prophylaxis, and the majority had impaired
In SPORTIF III, warfarin, shown in gray,
displayed an event rate of 2.3 percent per year
compared to 1.6 percent per year with ximelagatran,
shown in yellow.
In SPORTIF V, the rates were 1.2 for
warfarin, in gray, and 1.6 for ximelagatran, in
Primary event rates with ximelagatran are
nearly identical in SPORTIF III and SPORTIF V. For
warfarin, the rates fall within the range of event
rates in previous trials, 0.6 to 4.1 percent per
For comparison, the pooled rate
stroke trials for patients in this risk category
taking placebo or aspirin was over 8 percent per
year. The difference in event rates in SPORTIF
III, 0.66, favoring ximelagatran, had an upper
confidence limit of 0.13, less than the
prespecified 2-percent margin. In SPORTIF V, the
difference of 0.5 favoring warfarin had an upper
bound of 1.03, also less than the prespecified
2-percent per year margin. Thus, each trial
independently succeeded by satisfying the
prespecified noninferiority criterion for the
As expected, most of the events in this
composite outcome were ischemic strokes.
Hemorrhagic stroke and systemic embolism occurred
more rarely and did not influence the primary
Several sensitivity analyses confirmed the
results of the primary analysis. One such
analysis, depicted here, included all-cause
mortality in the primary endpoint at the suggestion
of the agency. SPORTIF III returned event rates of
4.2 and 5.1 for a difference of 0.87 favoring
ximelagatran, while SPORTIF V rates were nearly
identical at 4.7 and 4.8.
Adding all-cause mortality shifted each
study's event rate difference point estimate to the
left in favor of ximelagatran.
Another sensitivity analysis, depicted
here, used an on-treatment approach using the same
endpoints and the same population, but not counting
events that occurred after stopping study treatment
for 30 continuous or 60 total days. The upper
bound of negative 0.18 indicates superiority in
SPORTIF III. The value of 1.2 in SPORTIF V
indicates noninferiority to well-controlled
For each trial, we also performed a paper
comparison of ximelagatran to placebo by factoring
in the results of the six prior stroke prevention
trials. We obtained original data from those
trials to utilize the same endpoint events as in
SPORTIF. Demographics of patients in these trials
were similar to those of SPORTIF
In these calculations, SPORTIF III and
SPORTIF V separately demonstrated statistically
significant risk reductions for ximelagatran
relative to putative placebo, as did the pooled
SPORTIF data. Ximelagatran works as an
anticoagulant in this population.
As before, here we see differences in
primary event rates according to demographic
subgroups. These pooled results reveal no
discrepancies in any particular subpopulation,
including the elderly, women, the obese, and those
with poor renal function.
In conclusion, for atrial fibrillation
each of two trials independently met its objective,
demonstrating that 36 milligrams of ximelagatran
taken twice daily prevented stroke and systemic
embolism to an extent similar to that of
well-controlled anticoagulation with warfarin.
For long-term secondary VTE prevention,
the THRIVE III trial demonstrated that 24
milligrams ximelagatran twice daily prevented VTE
recurrence compared to placebo.
And in total knee replacement surgery, the
two independent EXULT trials showed that 36
milligrams twice daily prevented VTE and all-cause
mortality better than dose-adjusted warfarin.
Based on five pivotal trial, each the
largest in its field, involving more than 12,000
patients, these data establish the effectiveness of
ximelagatran as an oral anticoagulant in a variety
of patient populations at high risk for
Dr. Sunita Sheth will next address
particular safety aspects of administration of
ximelagatran for these indications.
DR. BORER: Thank you very much, Jay.
Again, we'll take a minute to see if
anyone has any issues that require clarification.
Clearly, we are going to talk about or probably
we're going to be talking about the selection of
the delta for the noninferiority trial, but I don't
want to get into that discussion now. We have some
extraordinary statistical fire power here between
Tom on the committee and Lloyd Fisher and
Faich sitting over there and the FDA statisticians.
I think we'll wait on that until after all the
presentations, including the FDA presentations,
have been made. But if we have any issues of fact
that need to be clarified now, let's do it.
DR. SACKNER-BERNSTEIN: In the FDA
briefing document, it points out that there were
patients who were withdrawn from the study for whom
there is not information about whether they
underwent or suffered any events. If that's
correct, please clarify, because it looks as though
from the study flow that that means in SPORTIF V as
many as 15 percent of the patients we basically
would not have any clinical outcomes data available
from the point in time when they withdrew. Is that
DR. HORROW: We followed up on all of our
patients in the SPORTIF III and V trials to the
greatest extent possible, and, in fact, after we
were done with our follow-up, at the time of final
closure, locking the database, we were
left, out of
7,922 patients, with only 63 patients about whom we
were unsure of their final status.
DR. SACKNER-BERNSTEIN: So that would mean
that the FDA briefing document is incorrect,
because the FDA briefing document states that--and
I'm looking at page 36 of the clinical review from
Cardio/Renal Division. It says in the first
paragraph that patients that were discontinued from
study medication and withdrew from study were not
followed for primary efficacy endpoints or death.
And then as you turn to page 45 with the patient
disposition in SPORTIF V, it looks as though
there's 300 study withdrawals from the ximelagatran
group and 286 from the warfarin group. So that
means that about 15 percent would have incomplete
clinical outcomes data, but you're saying there's
So could you explain for us where the
disparity should be settled?
DR. HORROW: It is conceivable that there
is a misinterpretation of the term "study drug
"withdrawal from study." More
likely, the misunderstanding may accrue from the
follow-up efforts that we made to ascertain the
vital status of every patient in the SPORTIF
We followed up on every patient, aside
from the 63 that I just mentioned, and are
confident in their vital status, knowing whether
they were alive or dead, whether they had a stroke
or not, in our database.
DR. FLEMING: Could I just clarify? So I
assume what you then did is you defined a date of
data lock or closure where on that calendar date
you wanted to follow all patients relative to their
survival status and stroke status. Are you saying
then for all but 63 patients you knew their
survival status and stroke status as of that
calendar date for data lock?
DR. HORROW: Exactly, and that would be
the data lock date for each respective
trial--SPORTIF III and SPORTIF V. That is correct.
DR. BORER: Steve?
DR. NISSEN: I want to make sure I
understand how you maintained the blind,
particularly in SPORTIF III. Obviously with
warfarin, you may require frequent dose adjustments
and so on. So in the open-label, particularly
SPORTIF III, how did you maintain--in both trials,
I'd like to understand the procedures that were
undertaken. I guess in the open-label trial there
was no blinding, right? The physicians and
patients knew what they were receiving; is that
DR. HORROW: In the open-label trial?
DR. NISSEN: Yes.
DR. HORROW: It was open-label dosing, and
so you are correct that the physicians and the
patients knew the drug, and the evaluators, the
neurologists locally, and the central adjudication
committee were blinded and didn't know.
DR. NISSEN: Okay, I understand. And
SPORTIF V, then, how did you adjust warfarin and
maintain the blind? Explain to me how that was
DR. HORROW: It was quite tricky and
involved quite a bit of work on the basis of the
investigators and quite a burden for the patients.
In SPORTIF V, all of the INR values were obtained
in almost all cases by only two
laboratories--that's an incredible degree of
standardization for thromboplastin--either the
centralized laboratory or a point-of-care machine
that had standardized cards.
In each case--well, for the point-of-care
machine, a coded number was produced by the
machine. That was called in to a central
randomization area, and that service then faxed to
the site either the true INR value if the patient
was really in the warfarin group or a shammed INR
value if the patient was truly taking ximelagatran.
So the site was unaware when it received the fax
what group the patient was in.
If the test was done at the centralized
laboratory, then the centralized laboratory
likewise sent the results to the IBRS site, the
specialized service, which then, again, faxed
either the shammed or the true INR value
DR. NISSEN: And then dose adjustments,
how were those then made? I mean, obviously some
of the patients needed a dose adjustment, so what
DR. HORROW: Well, as you know, for
ximelagatran or its placebo there were no dose
adjustments. But for warfarin or its placebo, each
investigator adjusted the dose based on their usual
practice considering the patient and the INR value
or shammed value--they didn't know which it
was--they'd received by fax.
DR. NISSEN: So there was no--it was all
done per local physician practice. There was no
standard applied to how dose adjustments were made.
Is that right?
DR. HORROW: That's correct. We did not
require all the investigators to adjust their
patients' warfarin doses against some standard.
This was to be a very real-world--as much as we
could--type of adjustment in terms of warfarin or
DR. NISSEN: And I assume the reason you
didn't do that in SPORTIF III was that you just
felt it was too difficult.
DR. HORROW: In SPORTIF III, the
investigators were very uncomfortable with blinded
anticoagulation testing and were unwilling to move
forward in that regard.
In SPORTIF V, our North American
investigators embraced the randomization somewhat
DR. NISSEN: So you tried to do SPORTIF
III blinded but they wouldn't go along with it? I
don't understand exactly what happened.
DR. HORROW: It was not possible to get
the investigators in SPORTIF III to move forward
with the blinded testing and anticoagulation.
DR. NISSEN: You attempted it, and then
they weren't able to comply. Is that what
DR. HORROW: At an investigators meeting,
DR. NISSEN: A rebellion.
DR. HORROW: There was no support.
DR. BORER: Okay. Bill? And then we have
Tom and Alan and John.
DR. HIATT: A comment and a question. In
the knee replacement studies, you commented that
you achieved a rapid increase in INR and that it
was 2.4 at day 3. And I just want to comment that,
you know, there's an association between
antithrombotic and anticoagulant effects of
warfarin. It takes 4 to 6 days for Factor II to be
depleted, so that's a false sense of security
around the measurement of the INR. They're still
So my question is: If you take the
three-quarters of patients at the end of that study
who were, quote, therapeutic versus the one-quarter
that were not, did you look at a subgroup analysis
around difference in VTE rates at the end of that
time? Were the patients who were, in fact,
therapeutic by that number equivalent in terms of
VTE rates compared with the patients who were
DR. HORROW: My understanding of the
question is did we perform a subgroup analysis near
the end of the treatment interval regarding
patients--or based on the actual INRs of the
patients. We do not have that analysis.
DR. HIATT: I think the speculation would
be that the differences would be erased in those
who were therapeutic, and a major difference
between treatments would have been in those who
were sub-therapeutic. That was my question.
DR. HORROW: This is quite possible, and
it's important to understand that the EXULT trials
mimicked warfarin administration in the orthopedic
surgery realm as it is currently practiced today in
the United States. And so it was a very relevant
way to look at the effects.
DR. BORER: Tom?
DR. PICKERING: Can you tell us how the
INR control rates in the SPORTIF trials compared
with the same rates in the six
DR. HORROW: The INR rates in the six
index trials had somewhat of a spread, as would be
expected, and it's actually possible to see that as
the INR rates are better in some of those trials,
so are the results in terms of the decrease in the
warfarin event rate. And our results for INR
control were really quite in the middle, 2.5,
2.4--could we have the previous slide, please? I
can show you some data on them.
This would be for SPORTIF V, summary
statistics. Please note in the middle column
labeled ximelagatran, we are looking at shammed
values, and you will note that we have 2.5 at 3
months for ximelagatran and 2.4 for warfarin, at 12
months similarly, at 24 months similarly--right in
the middle of the desired interval. And, of
course, the other thing that you might note here is
that there is a threshold of 4.0 for the shammed
values to ensure that no shammed value ended up
putting a patient unnecessarily in the hospital
because of an elevated shammed INR.
Nevertheless, as you can see by the ranges
here, it's quite clear that the
be unable to determine whether a patient were in
one group or the other.
DR. PICKERING: That really wasn't my
question. I was asking if there are comparable
data for the six warfarin placebo trials.
DR. HORROW: I don't have those data
available to show you at this time.
DR. BORER: I think they're in one of our
two books, Tom.
DR. HORROW: I believe they may be in the
DR. BORER: If I remember correctly, they
do show a fairly wide range, as you might expect,
but we can get those data.
DR. HIRSCH: I have two questions. One is
to follow up Steve's question regarding the SPORTIF
III blinding. I just always believe it's terribly
important to have blinding as a component of major
pivotal trials, acknowledging that lack of blind
can really alter outcomes in unexpected ways. So I
want to just run this through one more
Pitying the investigators that would not
go along with your request, the patients knew their
study assignment, correct?
DR. HORROW: In SPORTIF III.
DR. HIRSCH: In SPORTIF III.
DR. HORROW: That's correct.
DR. HIRSCH: The physicians--
DR. HORROW: The patients knew their
assignment, as did the principal investigators.
DR. HIRSCH: And coordinators.
DR. HORROW: That's correct.
DR. HIRSCH: So how would we have any
confidence that the adjudicating neurologist would
have any blind maintained at all?
DR. HORROW: Well--
DR. HIRSCH: I worry.
DR. HORROW: Your point is well taken that
that cannot be assured with certainty. We can say
that there were efforts made to make sure that the
neurologist was not told on purpose the assignment
of the patient, and we know also that all members
the central adjudication committee, which
evaluated all the endpoint events upon which the
results are based, did so in a totally blinded
DR. HIRSCH: I guess if there was
concordance between those two groups, I'm somewhat
Let me come back with a follow-up question
for EXULT, if I could. The data that we have
demonstrates benefits of ximelagatran versus
Coumadin preventing DVT in this population at risk
after total knee replacement. And as we'll discuss
later, most of that data is regarding distal DVT,
which I do care about. But in the database, do we
have any evidence, quality-of-life measurements,
girths, anything that demonstrates a clinically
relevant effect for the patient? In other words,
in the absence of venographic surveillance, would
the patient know there was a difference in outcome?
DR. HORROW: I'd like to ask Dr. Scott
Berkowitz, who is the medical director for that
particular trial, to address that issue. Dr.
DR. BERKOWITZ: Hi. Scott Berkowitz,
AstraZeneca. There was not any type of
quality-of-life assessment in this short-term
trial. The symptomatic events were collected as
well, including distal, proximal, and PEs. They
were low, as they are in TKR trials and did not see
a difference, a statistical difference.
DR. BORER: There was a question I was
going to hold until the end, but it seems to be
relevant right here in view of Alan's point. You
probably have a back-up slide, and Alan just
suggested that he probably has the data off the top
of his head. But can you tell us, among people
historically from older trials where data would be
available who have asymptomatic distal DVT and who
aren't treated, what's the risk of subsequent
thromboembolic events during some follow-up period?
DR. BERKOWITZ: Well, we don't have the
greatest data on that, unfortunately, in the
literature. What we know is that 10 to 20 percent,
depending on what you're readings--there are only
three or four studies--do propagate from
proximal. We know about 5 percent propagate to PE.
We don't know the actual recurrence rate of what
further DVTs would be after, say, 6 months. We do
also know that post-thrombotic syndrome occurs in 5
percent of patients in 2 to 7 years after total
knee replacement. Those are the real data that we
have. Not an area well studied.
DR. BORER: Jonathan, and then Steve.
DR. SACKNER-BERNSTEIN: I noticed that in
the trials for the study flow of patients in
several of your trials, including THRIVE, both
EXULTs, and SPORTIF V, that there is a number of
patients listed as being enrolled and then a second
number of patients listed as being randomized. And
there's very little information in either the FDA
or the sponsor's documents about what happened to
those patients. So I'm wondering if you could
describe it because in each of the cases you're
looking at probably in the range of 10 percent of
the patients who are enrolled that don't make it to
DR. BERKOWITZ: Maybe I'll first try to
answer for the EXULT and THRIVE, and then ask Dr.
Horrow for atrial fibrillation.
For the EXULT trials, patients were
enrolled, meaning that they were seen as an
outpatient up to a month before the procedure, and
then would come into the hospital, and if they had
the surgery of interest, which was primary total
knee replacement, then would be randomized,
assuming they went through the eligibility
criteria. The most common reason patients wouldn't
go from enrollment to randomization is that either
the--there were two: one, that the surgery was
cancelled, and then the patient wasn't rescheduled
for the procedure--excuse me, for the study, but
did do the procedure; the other was that with these
trials rapidly enrolling, we had many people lined
up but then the study--we reached our enrollment.
Those were the two major causes.
For the THRIVE study, these were patients
who had acute events for 6 months treated acute DVT
and then went on to a 6-month--either placebo or to
ximelagatran 24-milligram arm, and most
of these in
terms of just taking a look here--I can just show
you what we've got in terms of that. In terms of
the ones that were not randomized, there were 123
of those patients, and most of this turned out to
be eligibility not fulfilled or withdrawn consent.
And that is a common thing that patients might
think more about the study if they want to
participate in such a long-term--and then I could
turn it over to Dr. Horrow.
DR. HORROW: In the SPORTIF trials, the
major reason why patients were enrolled but not
randomized was because of the failure of an
eligibility criterion; in particular, the major one
was the ability to achieve two electrocardiograms
demonstrating atrial fibrillation in the manner
specified. And as a result, the principal
investigators did not enroll a number of the
patients whom they at first thought were good
DR. SACKNER-BERNSTEIN: Can I just follow
up? One quick point in follow-up. In the patients
enrolled in SPORTIF where many of them
off the vitamin K antagonist, how many--even if it
was a minority, how many of those patients had some
sort of clinical event that led them not to be
DR. HORROW: I understand your interest is
in seeing what happens to the patients who came off
of vitamin K antagonist in the enrollment period,
did they happen to have events. I believe that we
have some data on that, although I can't say for
sure that all of these did not enroll. They may
have had an event after enrollment. If you'll just
give me a moment, I'll see if we can find these
Yes, thank you. Here we see the number of
patients with primary events who had an event
within 30 days of discontinuing study drug, and
this would be either the ximelagatran or the
warfarin group. And this would be during the
course of the trial. As you can see, there's not
much difference between the two groups.
I think this may address the question that
you're getting at, which is what happens
patients discontinue their anticoagulant.
DR. SACKNER-BERNSTEIN: Well, actually, I
find that reassuring, that information, but really
what I was getting at was the impact of the
strategy that would be proposed based on the study,
which is you have a patient who's on long-term
warfarin and you're going to convert them
potentially to a new agent. There's a period that
would be followed where there's a transition, and
I'd like to know if that transition period is a
period that could be associated with risk as well.
DR. HORROW: I understand better. Thank
you. Here are some data from SPORTIF III looking
at primary events within 7 days of randomization.
There were three patients who had a primary event
in the SPORTIF III trial within 7 days of
randomization, and, of course, the patients taking
VKA--all patients had to stop their VKA in order to
begin randomization. And there were two events in
the warfarin group and one in the ximelagatran
DR. BORER: Steve?
DR. NISSEN: I want to come back to the
blinding issue again, and we've been dancing around
it so let me just come to the point.
Something extraordinary happened in
SPORTIF III and SPORTIF V. In SPORTIF III, I
calculate a hazard ratio of 1.39, 1.40 that's in
favor of ximelagatran. And in SPORTIF V, the
hazard ratio is 1.35 in favor of warfarin. And so
you have almost a completely opposite effect on the
point estimates, which, you know, is really unusual
when you consider the similarity of the trials.
So we're al trying--we're all sitting here
looking at the briefing document, and we're trying
to figure out what could possibly have happened
here so that, you know--I mean, there's essentially
a 39-percent greater risk for warfarin in SPORTIF
III and a 39-percent greater risk for ximelagatran
in SPORTIF V. And the only big difference in the
two trials is that one was blinded and one wasn't.
And so most rational people who look at
that would say, well, we're going to believe the
blinded results, we're not going to
unblinded results. And so this is a real
credibility issue, and I think we might as well
just put it on the table and get your reaction to
DR. HORROW: In fact, there are many
differences between SPORTIF III and SPORTIF V that
are confounded with the open-label and double-blind
nature of those two trials. The first and foremost
is geography, namely, that one study was conducted
in Europe and Asia and the other in North America,
and practice issues may pertain.
Secondly, although SPORTIF V patients more
often had hypertension, their blood pressures were
6 mm mercury lower, on average, than patients in
And, third, there was an artificially
intense control of INRs in SPORTIF V relative to
SPORTIF III, because in SPORTIF III there were over
270 clinical laboratories conducting INR
measurements, but there were essentially two in
SPORTIF V, achieving some kind of standardization
that is difficult to quantify.
Another aspect that is important to
consider is that the ximelagatran rates were
identical in the two trials. And in the warfarin
trials--I'm sorry, in the two trials, the
ximelagatran rates were identical, about 1.6. The
warfarin rates appear disparate. But those rates
are actually within the range of rates that are
seen in prior stroke prevention trials.
What we may be looking at here is another
manifestation of the variability of warfarin. This
slide shows in yellow the warfarin rates from the
six index trials, in orange the two rates from the
SPORTIF trials, and in dark brown the meta analysis
rate for the trials in yellow. And as you can see,
the SPORTIF rates are within the range of the
warfarin rates from the previous trials.
I hope that gives some perspective.
DR. FLEMING: Could you put that slide up
again? Can I follow up?
DR. BORER: Sure. Let me just put some
ground rules here, though. Steve has highlighted
what will be one of the key issues for
later on, and rather than get into it in great
detail here and get bogged down for the next hour,
perhaps we can deal only with issues of fact, and
then we'll get into the evaluation of those facts a
little bit later.
But with that in mind, go ahead, Tom.
DR. FLEMING: If you could put that slide
up, I just think for clarification, I don't think
that the point you just raised really answered
Steve's question. Steve's question had more to do
with the heterogeneity in the relative risk
estimate across to pivotal studies. This is
getting at the heterogeneity of the control arm
event rates across trials. And, in fact, those are
different phenomenon. This really gets at the
unreliability of noninferiority comparisons because
of this tremendous heterogeneity, which is a
While I have the mike, could I ask a
question that I had in mind? That is, one of the
things that's always concerned me in trials with
venograms is that we end up with a lot of
data, far more than what this committee would be
used to accepting in a manner to maintain integrity
of randomization. I think you had 20 and 15
percent, respectively, missing the outcome
assessments in EXULT A and EXULT B.
With that in mind, and also wanting to
really focus on what are not surrogates but true
clinical endpoints, endpoints that reflect tangible
benefit to patients, I struggle to look for what
are those measures that are really tangible that
are measured uniformly in patients. Could you show
Slide CE-19 as we look at EXULT A and B? Two of
these measures are pulmonary embolism and death
that should be assessed, I'm assuming, and
available in all patients. Your survival figures
here reflect, if I pool here, five deaths against
three. The agency on page 26 of their briefing
document has ten against four, so you're missing
five deaths in the Exanta arm and one in the
warfarin arm. Could you clarify that discrepancy?
DR. HORROW: If I may first address the
issue of the heterogeneity, then we can
go on to
the issue with EXULT.
If I'm not mistaken, you're referring, in
terms of the heterogeneity in SPORTIF, to what may
be called a study by treatment interaction, the
difference in sampling and getting one set versus
the other. And I think it's important to
understand that in each case, noninferiority was
satisfied; that is, looking at the data just in
those terms and how those numbers are sorted does
not take into account the noninferiority design of
the trials and that the success is determined by
whether or not it meets the noninferiority
The heterogeneity result which we've
looked at is not robust to sensitivity analyses
like the primary results are robust. So, for
example, if one looks at primary events plus
all-cause mortality, which was an endpoint
suggested by the agency, the heterogeneity
disappears and the p value is 0.23. And if you
look at other prespecified outcomes, such as major
bleeding, there's no suggestion of
The heterogeneity p value is 0.81. For total
bleeding it's 0.275.
And so we view the idea of disparate
results in the two trials with some suspicion and
think that we need to be very careful how we
interpret those primary results in terms of being
disparate or the same. We view them as sampling
from the same pool and getting two separate results
and that the best estimate of the data comes from
I'd like now to--
DR. FLEMING: Given that you didn't answer
my question and you provided a different answer,
let me respond to the answer you just gave. The
question that Steve asked is why was there such
heterogeneity in relative risk estimates. The
answer that you gave was there's a lot of
heterogeneity in the control arm, in the warfarin
rates across trials. Logically, I would assume
that if you're saying when the warfarin rate in
truth is different across trials, we should expect
different treatment effect, it really makes me
worry about doing a noninferiority trial where you
have to rely on historical evidence.
Could you answer, though, the question
that I'd asked here about the discrepancy between
your data here and the FDA briefing document?
DR. HORROW: I'd like to ask Dr. Scott
Berkowitz, who was the medical person for this
particular trial, to address this issue.
DR. BERKOWITZ: Yes, Scott Berkowitz,
AstraZeneca. I just wanted to say in terms of the
venography rate--I have the data to show you, but
in terms of venograph, these two trials had the
highest adequacy of evaluability ever done in
clinical trials for pivotal purposes.
DR. FLEMING: That may be, and yet the
reality is we're still lacking 15 to 20 percent of
our randomization cohort, and we no longer are
assured of integrity of randomization. So could I
get the answer to my question?
DR. BERKOWITZ: So for what you saw, those
data that you saw in the briefing packet were for
the overall study, so you can see it's
four, but I'm going to--could I have the next
slide?--show you the breakout for treatment, which
is the primary endpoint--
DR. FLEMING: So, in fact, what I do want
is the entire study, ten and four. So is the
clarification CE-19, then--
DR. BERKOWITZ: Could we go back?
DR. FLEMING: Then the reason CE-19 is
leaving out the five deaths and one death is that
those occurred in the non-80, 85 percent?
DR. BERKOWITZ: The deaths--I'm sorry.
Say that again? I'm sorry.
DR. FLEMING: What is the reason that your
slide here leaves out five deaths and one death?
DR. BERKOWITZ: That slide showed the
primary endpoint which included the treatment
period of day 7 to 12 days as opposed to the
overall, which showed only this study and the next
one, if you want to see the breakout.
DR. FLEMING: Good. And so that is--could
you show it again?
DR. BERKOWITZ: Oh, yes.
Can I see the
next one? Thank you. We want to see now the
breakout between the treatment--
DR. FLEMING: So that the total deaths are
as here, they are as there in the FDA briefing
document, ten against four in the wrong direction.
And pulmonary embolism is, according to the FDA
briefing document, four against five as reported by
DR. BERKOWITZ: Yes. Well, you can see
down--for the treatment period, as you can see,
there was one in the ximelagatran 36 group and none
in warfarin. During the follow-up period, there
were four in the ximelagatran group and zero in
DR. FLEMING: And so in an ITT analysis
that does include all patients and focuses on,
among the most clinically relevant endpoints, death
and pulmonary embolism, it appears that there are
actually numerically an excess of events in the
Exanta group. By my count there are 15 events
against 10 events, and that's your numbers as well.
Is that correct?
DR. BERKOWITZ: Well, except that the
numbers that you're seeing in follow-up are after
patients are off treatment but they get seen in 4
to 6 weeks.
DR. FLEMING: I want ITT, and that's what
it looks like. Is that correct? It's 15 against
10 in the wrong direction? Just is the FDA summary
correct on page 26?
DR. BERKOWITZ: Yes.
DR. FLEMING: And one other quick
question, if I could. Again, wanting to try to
focus on an ITT of a critical endpoint, all-cause
mortality, in THRIVE III could you show us the ITT
summary? This is the placebo-controlled trial
where we see a substantial efficacy result on the
symptomatic endpoint. Could you show us the ITT of
the survival curves for that trial?
DR. BERKOWITZ: I'm not certain--did you
want to see the slide that we showed for the
DR. FLEMING: I believe it's corresponding
to the page 7, Figure 1 in your briefing
DR. BERKOWITZ: Let me bring that up. I
just want to be sure it's the same one that we saw.
DR. FLEMING: The one that I am in
particular looking for here, because that figure
includes all the data from all the trials, is in
particular THRIVE III with ITT analysis of
mortality over the time frame that you followed
DR. BERKOWITZ: Yes, okay, and that's what
we were--yes, I'm sorry. So here you go. This is
DR. FLEMING: Mortality.
DR. BERKOWITZ: Yes.
DR. FLEMING: All-cause, ITT.
DR. BERKOWITZ: I'm sorry. I still don't
understand what you--just the mortality slide?
DR. FLEMING: Yes, as you have in Figure 1
of your briefing document.
DR. BORER: You wanted to see only for
THRIVE, or you wanted to for the--
DR. FLEMING: Either way, if you--okay.
DR. BERKOWITZ: This is the slide in the
briefing document that you're speaking of with all
DR. FLEMING: Okay. And could you--so the
THRIVE is, in fact, the--
DR. BERKOWITZ: I'm sorry, yes, the THRIVE
is the lowest curve there, the ximelagatran versus
placebo in the lowest group.
DR. FLEMING: And so essentially, while
I'm focusing on THRIVE, the evidence here would
suggest, even in placebo-controlled comparisons,
there's strong suggestion of no differences in
DR. BERKOWITZ: Well, I mean, they're
lower with the ximelagatran group, but not a strong
DR. FLEMING: I'm sorry. I don't--the
curves look overlapping in the THRIVE III, and in
the other studies they are very overlapping as
DR. BORER: Steve?
DR. NISSEN: Yes, I just had one more
question, still trying to probe to
differences between SPORTIF III and SPORTIF V.
Could you show us the INR values, that is, the
degree of anticoagulation control in SPORTIF III
and SPORTIF V for the warfarin arms.
DR. BERKOWITZ: I'll ask Dr. Jay Horrow to
DR. HORROW: I'm sorry. I missed the last
two words in--
DR. NISSEN: Yes, I just want to see in
the warfarin arm of the trials, I want to see what
the INRs looked like in SPORTIF III and SPORTIF V.
DR. HORROW: Okay. I believe these data
will address your question. There were almost
100,000 different INR values, and this summary
perhaps helps. Here we have SPORTIF III and
SPORTIF V and the percentage of time in specific
DR. NISSEN: It does.
DR. HORROW: Okay. Thank you.
DR. BORER: A final question of fact,
DR. SACKNER-BERNSTEIN: I think the key
thing is that all of the slides that show ITT are
not true ITT analyses. It's not just THRIVE. It's
THRIVE and EXULT, and they list that in the
briefing document. There are a lot of numbers
where those are different, so we should just
interpret it that way.
DR. FLEMING: It was part of the reason
for my asking the question. I wanted to get a
verification that we were being shown, for
endpoints such as mortality, a true ITT. And I
understand that they're telling us they are showing
us a true ITT where you have uniform follow-up
through a given calendar date at which the study
data freeze would have occurred, and you would have
complete follow-up on mortality for all patients.
Is that what that Figure 1 showed?
DR. HORROW: Yes.
DR. BORER: Okay. Thank you, Jay.
DR. HORROW: May I introduce Dr. Sunita
Sheth, who will discuss particular aspects of
safety for ximelagatran.
DR. SHETH: Good morning.
Sheth, Senior Director of Clinical Research at
You've just seen the efficacy data
supporting the benefit of ximelagatran as an oral
anticoagulant. I'll now review the clinical safety
date. The analysis comes from a large data set
with more than 30,000 subjects, many of the
patients involved having serious underlying disease
and receiving multiple drug therapy.
First, I'll discuss by indication the
adverse events and bleeding profiles. Efficacy for
any anticoagulant is balanced by risk of bleeding.
Indeed, bleeding and the prevention of thrombosis
derive from the same action of drug. That's why
bleeding was a prespecified endpoint in the pivotal
trials. And major bleeding was adjudicated in a
blinded fashion in all Phase II and Phase III
trials. Then I'll focus on two specific topics:
myocardial ischemic events and the hepatic
findings. Finally, I'll conclude with a review of
overall mortality and summarize the key points for
It may help if I display how we've
organized the large data set. It divides logically
into three groups: Phase I, surgical, and
nonsurgical populations. The Phase I population,
composed primarily of healthy volunteers dosed for
up to 8 days, didn't present any safety signals.
Surgical patients, mostly from the orthopedic
studies with dosing up to 12 days, have different
safety issues, in particular, perioperative
bleeding, and so they are reviewed as a separate
The nonsurgical population primarily
received drug for more than 35 days and provides
the core safety evaluation of long-term dosing,
with exposure up to 4 years. Each population pool
is large, allowing a detailed assessment of safety
in each case.
I will first review the safety for the
surgical indication. The North American surgical
population has been termed "the warfarin comparison
pool" and provides the safety data for the
indication under consideration today,
post-operative dosing of either oral ximelagatran
or warfarin after total knee replacement surgery.
This pool includes data from three Phase III
trials: the two EXULT trials as well as an earlier
study evaluating 24 milligrams versus warfarin.
Overall, it includes 5,236 patients.
In all graphs, ximelagatran will be shown
in a shade of orange and the comparator in gray.
Here's the summary of adverse events for
the surgical pool. Both treatment groups showed a
similar frequency and type of adverse events.
There didn't appear to be any dose response
comparing the 24- and 36-milligram doses. We can
look more closely at the EXULT trials where both
major and minor bleeding events underwent
independent adjudication. Rates of major bleeding,
shown at the bottom of each bar, were 1 percent or
less in all treatment groups, with no statistically
significant differences for major bleeding alone or
for the combination of major and minor bleeding,
for which respective p values are shown.
When you look at the data for
36-milligram dose, there wasn't a difference in
surgical outcome parameters, such as wound hematoma
or intra-articular bleeding. Additionally, the
proportion of patients receiving transfusion and
the volume of transfusion were similar in each
Now, let me turn to the nonsurgical
patients who comprise the long-term dosing group.
This group is called the long-term exposure or LTE
pool, with patients from all the Phase II and Phase
III studies conducted so far involving dosing
beyond a month's duration. In addition to patients
from the atrial fibrillation and venous
thromboembolic secondary prevention indications,
we've included data from two other disease areas
where significant trials have been conducted,
patients undergoing initial 6-month treatment for a
venous thromboembolic event and patients post-acute
coronary syndromes. The overall ximelagatran
exposure is substantial, a total of 6,768 patient
years, with a median exposure of 370 days.
Across this population, doses
and 60 milligrams have been used, although the
majority of patients, 75 percent of them, received
36 milligrams twice daily. The comparator group
includes both placebo as well as warfarin and is
termed "the comparators' group." In this group, 20
percent of patients received placebo.
I'll now comment on the different
In the VTE extended prophylaxis pool, both
ximelagatran and placebo groups demonstrate similar
frequency and types of adverse events. The
incidence of serious adverse events and
discontinuations was actually lower in the
ximelagatran group compared to placebo.
In the same group, major bleeding occurred
rarely, affecting six patients in the ximelagatran
group and five patients in the placebo group.
Ximelagatran and placebo groups also did not differ
with respect to major or minor bleeding events.
In the atrial fibrillation pool, the same
frequency and types of adverse events were recorded
in both the ximelagatran and warfarin
Discontinuations were higher in the ximelagatran
group, not because of symptoms but mainly due to a
protocol-mandated discontinuation for ALT
elevation. I'll discuss this in detail shortly.
In the atrial fib population, the rates of
major bleeding with ximelagatran did not differ
from those with warfarin. Minor bleeding events
occurred quite often in these trials and for that
reason did not undergo adjudication. Here we see
the event rates for patients with one or more major
or minor bleeding events. Total bleeding occurred
significantly less often with ximelagatran than
with warfarin, with a p value of less than 0.001.
Overall, with regard to adverse events and
bleeding, ximelagatran compared to well-controlled
warfarin following total knee replacement surgery,
compared to placebo and extended secondary
prophylaxis of VTE, and compared to warfarin in
atrial fibrillation patients demonstrated no
important differences in adverse events, bleeding
profile, or the safety profile of the 24- and
36-milligram doses. In addition, a detailed
subgroup analysis for bleeding supports the
proposed fixed-dose approach for all types of
I'll now review two special safety topics,
coronary artery disease and the hepatic findings.
First let's address the coronary artery disease
The agency has noted a possible imbalance
in the frequency of myocardial infarctions. Shown
here is Table 12 from the FDA briefing document.
The events shown here are investigator-reported
events. Note that the absolute number of
myocardial infarctions observed in the EXULT trials
was small, and there appears in a post-hoc analysis
to be a significant difference with a p value of
0.049. However, this difference is driven by a
single trial, EXULT A. Furthermore, an analysis of
other coronary artery disease events failed to
reveal any significant difference.
FDA Table 40 shows investigator-reported
coronary adverse events from selected trials from
the long-term pool. This analysis suggested an
increased frequency of total coronary adverse
events in the VTE treatment population. When VTE
treatment and extended prophylaxis are evaluated I
a post-hoc pooling and analysis, the p value is
significant for both myocardial infarctions and
other coronary artery disease events. However,
this finding was not observed in the much larger
atrial fibrillation pool. In addition, the trial
in acute post-coronary syndromes where benefit was
demonstrated is not included in this analysis. In
fact, when all three groups are pooled, no
significant difference is observed for either
myocardial infarctions or other coronary events.
In addition to the investigator-reported
events, the SPORTIF trials in atrial fibrillation
with an active comparator, warfarin, and the ESTEEM
trial in the post-ACS setting versus placebo
provided an independent and objective assessment of
myocardial infarctions. In fact, adjudicated
events in these trials represent over 90 percent of
all MIs across the program. Here, evaluation of
the SPORTIF trials demonstrated an
incidence while the ESTEEM trial demonstrated an
actual reduction in myocardial infarctions.
It is also relevant in this context that
across the whole program we have no evidence of any
rebound effects producing MIs after ximelagatran
treatment was stopped.
So with regard to coronary artery disease
adverse events, while a concern was raised
regarding a potential imbalance in events, a more
comprehensive analysis focusing on both
investigator-reported and objectively assessed
events fails to identify an increased risk.
I now want to turn to the unexpected
results, the hepatic findings, and present a
We've taken the findings very seriously,
and from the large database individual case
analysis and consultation with hepatic experts,
we've produced a thorough assessment. I'll first
review the laboratory findings followed by the
adverse event data.
Preclinical toxicology and the
studies did not demonstrate any hepatic safety
issue. The surgical studies with up to 12 days of
dosing didn't show any hepatic changes with
ximelagatran, just the well-recognized enzyme
elevation seen with heparin. In the first Phase II
long-term dosing study with ximelagatran in the
atrial fibrillation patients, a signal of an
asymptomatic increase in ALT greater than 3 times
the upper limit of normal was noted. Therefore,
the standard laboratory testing that was being
performed early in the development program was
increased in the Phase III studies.
The liver function testing panel consisted
of alanine amino transferase, or ALT; aspartate
aminotransferase, or AST; alkaline phosphatase, and
total bilirubin. These tests were performed
monthly for the first 6 months of exposure, then
every 2 months up to one year, and then quarterly.
In addition, weekly testing and discontinuation
criteria were defined. These criteria were
strengthened after one case of biopsy-documented
As mentioned, there was no increase in ALT
greater than 3 times the upper limit of normal in
ximelagatran patients undergoing total knee
replacement compared to warfarin during treatment.
At the 4- to 6-week follow-up, there were eight
patients in the ximelagatran group and three in the
warfarin group that developed an increase in ALT.
In general, these increases occurred 3 weeks after
discontinuation of drug. It's important to note
that two patients with the transaminase elevation
in follow-up in the ximelagatran group had received
low-molecular-weight heparin. The ALT elevation in
all patients but one in each group is documented as
resolved. We believe that patients undergoing
orthopedic surgery with short-term dosing of
ximelagatran are not at an increased risk of ALT
elevations or liver injury.
Now, let me summarize the incidence of
enzyme elevations of the long-term exposure pool.
The incident of ALT greater than 3 times the upper
limit of normal was 7.9 percent for ximelagatran
compared with 1.2 percent for
comparators. It's of
interest to note that there was no difference
between groups for isolated elevations of
bilirubin. The vast majority of these enzyme
elevations were asymptomatic.
Our experience shows that the time
signature for ALT elevation follows a consistent
pattern. This graph depicts the number of patients
with first ALT greater than 3 times the upper limit
of normal over time. The y axis represents the
cumulative risk of an ALT greater than 3 times the
upper limit of normal and the x axis time in
months. As can be seen, the occurrence increases
above background rates after 1 month and approaches
background rates after 6 months. Ninety-three
percent were detected during the first 6 months,
and 98 percent within the first 12 months.
I now want to turn to the disposition of
patients with an ALT increase. Of the 546 patients
in the ximelagatran group that had an increase to
greater than 3 times the upper limit normal, 46
percent of patients continued to treatment and
completed the study. The other 54 percent
discontinued study drug. Overall, 96 percent of
ximelagatran-treated patients returned to less than
or equal to 2 times the upper limit of normal ALT,
regardless of continuation or discontinuation of
drug. Of the 74 patients in the comparator group,
31 percent continued treatment, and the other 69
percent discontinued treatment. Overall, 93
percent of comparator-treated patients recovered.
The algorithm allows continuation of
treatment for mild and transient increases on drug.
These data demonstrate the reversibility of the ALT
Patients who continued drug recovered by a
median of 28 days, and those who discontinued drug
by a median of 40 days. Eighteen patients were
rechallenged early in the program. Only two
patients had a subsequent ALT rise. One pt with a
peak ALT of 10 times the upper limit of normal was
rechallenged after 65 days and did not have a
repeat elevation until 2 months later. The second
peak was at 3 times the upper limit of normal, and
the drug was discontinued.
The second patient did not have a true
rechallenge, but had multiple episodes above 3
times the upper limit of normal, but overall
recovered with continuation of the drug. There was
no evidence in these or any other patients for an
Hepatic experts that we consulted
suggested that the elevation of ALT greater than 3
times the upper limit of normal and clinical
jaundice, in the absence of an alternative
diagnosis, can be considered a signal of severe
hepatic injury. We selected a more conservative
definition to standardize the levels and timing and
included cases with ALT greater than 3 times the
upper limit of normal and bilirubin greater than 2
times the upper limit of normal, the latter
occurring within one month of the ALT rise.
A total of 37 patients, or 0.53 percent,
in the ximelagatran group had this concurrent
elevation of ALT and bilirubin, compared with five
patients in the comparators' group, with an
incidence of 0.08 percent.
Please note that one additional case has
been included in this analysis at the request of
the FDA. We had fully documented this case
involving a fatal GI bleed in the submission and
had also highlighted it as a case of interest in
the safety review.
I'll now review the outcome in patients
with a concurrent increase in both ALT and
bilirubin. Confounding diagnoses were noted in 25
of the 37 patients on ximelagatran. Seven patients
in the subset died of unrelated causes. Twelve
patients did not have an alternative diagnosis for
the enzyme elevation. Of these 12, two died with a
GI bleeding event and will be discussed shortly.
The ALT and bilirubin in all other patients
recovered. Of the five cases in the comparator
group, four had an alternative diagnosis, and only
one had an unexplained increase. Two patients died
from pancreatic cancer. The other patients
We have been investigating a possible
mechanism for the hepatic changes, but so
has not been elucidated. Preclinical studies
evaluating reactive metabolites, mitochondrial
dysfunction, and protein binding have not been
revealing. There is no evidence for involvement of
the P450 system. The asymptomatic and
nonprogressive pattern of ALT increase has been
noted with other drugs, including tacrine, INH,
amiodarone, among others.
We wanted to understand if there's a
subgroup that's at increased risk. Because the
number of patients with concomitant ALT and
bilirubin is so low, this analysis was performed on
the occurrence of ALT greater than 3 times the
upper limit of normal. Therefore, these results
should be interpreted with caution. A step-wise
logistic regression was performed looking at
demographic factors, statin use, and baseline
disease. As expected, the most significant factor
in this analysis was ximelagatran treatment with an
odds ration of 6.82.
Other factors that demonstrated
statistical significance all had an odds
less than 2. These includes patients post-ACS,
patients being treated for an acute venous
thromboembolic event, body mass index less than 25
kilograms per meter squared, and female gender.
Statins and creatinine clearance were not
identified as significant factors.
The variable of ALT greater than 3 times
the upper limit of normal is generally asymptomatic
and reversible. Therefore, this analysis does not
allow a prediction for those at risk for severe
liver injury. We are, therefore, recommending ALT
testing for everyone who starts long-term treatment
Now let's look at the adverse event data
from these patients. No difference is noted
between groups for clinical hepatobiliary adverse
T2B I will now briefly review
three selected cases in the group of patients with
concomitant increase in ALT and bilirubin
associated with ximelagatran. These cases were
selected by the FDA as three deaths with
severe liver injury. The first two cases occurred
on the first algorithm, and the third case on the
second more conservative algorithm. The second and
third case did not demonstrate compliance with the
algorithm in effect at the time. The deaths in all
three cases are also confounded by other factors.
In the first two cases, the ALT and
bilirubin increase was unexplained, and the
terminal event in both cases was a GI bleeding
The first patient, an 80-year-old male,
had a hepatic biopsy with documented hepatic
necrosis about 1 month before death. This patient
had evidence of decreased hepatic function.
However, the ALT was recovering when he died from a
perforated duodenal ulcer. This patient had been
The second case presented hypertensive to
the hospital with an elevated ALT of 11 times the
upper limit of normal and a bilirubin of 1.4 times
the upper limit of normal after missing two weekly
tests for an elevated ALT. The INR was 3.4 and the
APTT was 69 seconds. His last dose of ximelagatran
had been earlier that evening. The patient had a
prior history of duodenal ulcer and Bilroth II
anastomosis with bleeding at the site detected on
this admission. During the 24 hours from the
admission to death, the patient received massive
transfusions. During this time his bilirubin
increased from 1.4 times the upper limit of normal
to 9.4 times the upper limit of normal, with 50
percent noted as indirect bilirubin. At the time
of death, the bilirubin was 7.3 times the upper
limit of normal and the ALT less than 2 times the
upper limit of normal.
The third case was a death due to
fulminant reactivation hepatitis B with an elevated
ALT upon study initiation. This patient was on two
immunosuppressive drugs: prednisone and
azathioprine. Ximelagatran was not discontinued
when the ALT reached greater than 5 times the upper
limit of normal as recommended. The patient had a
rapid and fulminant course attributed to the
hepatitis B. However, the investigator could not
rule out that the drug did not contribute to the
To summarize the hepatic findings, ALT
elevations greater than 3 times the upper limit of
normal occurred in 7.9 percent of
ximelagatran-treated patients, occurring primarily
within the first 6 months. The elevations were
typically asymptomatic and reversible, without any
evidence of an immunoallergic reaction. An
incidence of 0.5 percent of concurrent ALT greater
than 3 times the upper limit of normal and
bilirubin greater than 2 times the upper limit of
normal was observed. Exposure response suggests
that exposure is not predictive of individual risk
of transaminase elevation, and no patient subset
was identified to be at higher risk of developing
severe hepatic injury.
Based on the data, we are proposing ALT
testing in the label reflecting the more
conservative testing schedule used in clinical
trials. To make sure that ALT testing becomes the
standard of care with ximelagatran, we
submitted a risk minimization plan which set out
our initial proposals to support ALT testing in
practice. This proposal was developed after
extensive external consultation and field testing,
but we recognize that it may need to be developed
further in the best interests of ensuring patient
safety. We have a meeting arranged with FDA on
this topic in the near future.
A few comments on the principles of our
Risk Minimization Action Plan. The ultimate goal
of the plan is to prevent any hepatic failure
caused by treatment with ximelagatran. To do this,
the Risk MAP will help to ensure compliance with
labeled ALT testing recommendations. This proposal
was developed to provide access to ximelagatran by
those patients who will benefit while minimizing
risk. It targets patients, physicians, and
pharmacists. It has a strong educational focus and
is enhanced with practice management tools and
special packaging. In addition, following
discussions with FDA, AstraZeneca will be proposing
additional enhancements to ensure our ALT
recommendations are followed. Finally, we have
proposed continuous evaluation of program
AstraZeneca understands that the full
benefit of ximelagatran can only be realized if it
is used in accordance with the labeled recommendations, and
to that end we are committed to
developing the specifics of the program in
consultation with the agency.
To complete the assessment of safety, we
will finish with the overall mortality in the
long-term exposure pool to get an overview of risk.
The patient population was primarily an elderly
population with multiple comorbidities and
concurrent medications. Despite an increase in ALT
in the ximelagatran-treated patients, no difference
in all-cause mortality was noted. Mortality was
similar in the ximelagatran group compared to
patients on placebo, patients on placebo plus
aspirin, and patients on warfarin.
Let me finish by summarizing the
benefit/risk comments for each
Ximelagatran prevented venous thromboembolism
and/or all-cause mortality compared with warfarin
in total knee replacement surgery with a number
needed to treat of 12. No difference was seen in
bleeding, transfusions, or surgical outcome.
Ximelagatran demonstrated clear benefit
over placebo with a number needed to treat of 10 in
the long-term prevention of recurrent VTE events.
This included a clinically important reduction in
pulmonary embolus, a condition that can result in
serious morbidity and mortality. The incidence of
bleeding was comparable to placebo.
Ximelagatran was as effective as warfarin
in reducing the risk of stroke and other
thromboembolic events in patient with atrial
fibrillation. Bleeding was lower on ximelagatran.
With regards to the hepatic findings, while the
risk per year for stroke or venous thromboembolism
is continuous, the risk for an ALT rise and
subsequent severe liver injury is limited primarily
to the first 6 months of ximelagatran therapy. But
the protection from a thrombotic event by
ximelagatran is continuous and consistent over
To aid effective management of the hepatic
risk, ALT testing will be recommended in our
proposed labeling, and in addition, we have
submitted a Risk Minimization Action Plan which we
will discuss further with the FDA.
We conclude that ximelagatran, the first
new oral anticoagulant in over 50 years, does have
a positive benefit/risk in each proposed indication
provided that the drug is used properly. We look
forward to your comments and further dialogue with
Thank you. I'll take questions.
DR. BORER: Dr. Sheth, I think we need to
take a break. I've been chastised when we haven't
done that. So we'll take a 10-minute break, and
then we'll go on to the questions of fact about the
safety data, and I think we can then go on to
Jonathan Halperin's presentation, and we'll just
make up the remaining FDA time after the public
comments later so that you can get your
So we'll take a 10-minute break right now.
Look at your watch because 10 minutes from now
we're going to start again.
DR. BORER: While everybody is getting
back in here and sitting down--or not sitting
down--let me raise an issue for you to begin to
think about as people are coming back in.
Steve Nissen asked earlier about
pharmacological evidence of rebound, and there
didn't appear to be significant rebound, although I
don't know what that means in the context of
studies with limited power. But there didn't seem
to be significant rebound of pharmacological
effects, although the follow-up, as I recall, was
relatively short. So we don't know about late
pharmacological changes. But as I look at these
data from each of the trials, I'm struck with a
difference between the on-treatment and
post-treatment frequency of major adverse
cardiovascular events that I'd like to
discussion about from you. Is this real or is it
not? That is that if you look at the number of
myocardial infarctions or other cardiac events that
occurred on ximelagatran versus the comparator, the
numbers were different but not all that different.
It depended on the trial. It varied from trial to
trial, and we can talk about that potential adverse
event disparity later. But I'm concerned or I want
to ask about something else.
If you look at the number of events that
occurred on-treatment, the numbers were relatively
close one way or the other from trial to trial to
trial. If you look at the numbers that occurred
post-treatment, the proportion of patients who had
events on ximelagatran in the post-treatment period
was greater as a percentage of the whole than was
the case for any of the comparators. The
post-treatment events on warfarin or on placebo
were fewer as a proportion of the whole of the
total number of events in those comparator groups
than was the case with ximelagatran, and in some
cases the post-treatment events were more
than the on-treatment events with ximelagatran.
That's an observation.
Have you noted that? And is that true?
And do you have anything to say about it?
DR. SHETH: The numbers differ a little
bit between the different patient groups. So let
me start first with the long-term exposure pool and
some of the specific populations within that pool.
If we can take a look again at the--and
we're talking coronary events, Dr. Borer?
DR. BORER: Yes, we can limit it to
coronary events, however they're defined.
DR. SHETH: What you see is that, you're
right, there is a difference--I'm sorry. Let's put
that up. You do see an increase--and these are
both myocardial infarctions and total other
coronary artery disease events other than MI
compared in the VTE treatment and the VTE extended
prophylaxis compared to warfarin. But these
numbers are actually quite small. We're talking
about a total of 16 patients here, 3, 16, 10, et
cetera, versus 1, 0, 12, 3.
If we take a look at two populations where
you might say that the risk is actually increased,
the atrial fib group had higher incidence of both
diabetes, hypertension, for example. You don't see
that--those events, again, plus that in the
post-acute coronary syndrome population, which is
certainly a high-risk group for events. Can we
take a look at the next slide? I'll come back to
the after-treatment in a second.
Ninety percent of the MIs--and this was
during the trials--occurred in these two settings,
and you don't see a difference there, and you see a
benefit on treatment with ximelagatran.
But if we take a look, let's say, at the
post-acute coronary syndrome population, again, a
higher-risk group, after treatment stopped, the
incidence between those two groups was about 1.5
percent--I think it's about 1.5 percent in both
DR. BORER: Okay. I'm sure you're right,
and the data you just showed I think are very
reassuring, and I think we all saw them
in the book
here. But, again, I'm making a slightly different
point, and maybe the data aren't available or
aren't sufficient to draw a firm conclusion about
What I am talking about is the proportion
of coronary events that occurred after stopping
treatment on ximelagatran as a percentage of the
total number of events compared with the portion
that occurred after stopping treatment with
warfarin or placebo as a percentage of the total
number of events in those groups. I believe that
the proportion of events that occur post-treatment
is higher in the ximelagatran groups across all the
trials, if you look at trial after trial, than is
the case for the comparators, which raises some
question about the possibility of a rebound
phenomenon or something else, some other
pathophysiological process that's being allowed to
happen or occurring because of the use of the drug
once it's stopped.
DR. SHETH: I understand what you're
We don't have that specific analysis, so I
won't be able to address it at this moment. You're
asking for those proportions of patients after they
stop treatment over the total number of events, and
right now I don't have that analysis.
DR. BORER: Okay. You can pull it
together later, but it's in the books. If you look
at the data that are presented, if you look at the
numbers, that sort of jumps out at you. So you may
want to look at that, and you can talk about it
after lunch or something.
DR. SHETH: Okay.
DR. BORER: Okay. Well, why don't we go
on and see--Alan?
DR. HIRSCH: Well, just one comment to
follow up Jeff, and if you're able to provide that
after lunch, I specifically would ask you provide
that not in the ACS population, because the
population that will be exposed to this if this
drug comes to market that really is vulnerable that
I'm concerned about is that non-ACS population.
DR. SHETH: Okay.
DR. HIRSCH: I don't want that to be a
Band-aid for a potential adverse effect.
DR. BORER: Steve and then Bill.
DR. NISSEN: Just so you understand what
we're concerned about--and several of us have made
this observation--it is that because ximelagatran
is a short-acting agent compared to Coumadin, our
worry is that when you stop the drug, there's some
phenomenon that goes on for a few days or a few
weeks in which a patient has increased vulnerability and
that that is the explanation for the
excess cardiovascular events. And we want to
understand whether you have some response to that
that we can factor into our thinking.
DR. SHETH: Can I ask, would it help the
committee to take a look at other thrombotic events
in terms of incident or rebound phenomena? Because
certainly patients who are usually at risk for
venous events might typically get those kind of
events. Would that help--
DR. NISSEN: It only helps a little bit.
The problem is that the pathophysiology of arterial
and venous events are different.
DR. SHETH: Right.
DR. NISSEN: And so, you know, it appears
that there is this excess of arterial thrombotic
events post-treatment, and we're trying to
understand that in order to factor that into the
thinking here of the committee.
DR. SHETH: Right, although in maybe the
treatment and prevention groups--
DR. NISSEN: Yes, yes. I have another
question, and forgive me for this, but I have to
probe on something that I think is important. If
you could put up Slide No. CE-19, please? I see
these patients that are going to have knee
replacement all the time in consultation. They
almost all get sent for cardiac clearance because
they're older and they have a lot of cardiovascular
risk factors, and I'll bet the other cardiologists
at this table, like Jeff probably sees plenty of
these as well. And so when I see them, there are
three things that I worry about. I worry about, of
course, them dying. I worry about them having a
pulmonary embolus. And I worry about them having a
And so, you know, to do the simple math
here, which is what all of us are kind of looking
at, if you look at the serious endpoints, the
feared complications, what you see is--in EXULT A
and B, you see three plus six is nine events with
ximelagatran, and you see eight events here, PE or
death, with warfarin.
If you now put up Slide No.--
DR. FLEMING: Steve, just before you go,
those nine and eight are 15 and 10 in the FDA
briefing document. It's worse than this. It's 15
DR. NISSEN: Okay. I'm trying to be--you
know, not make this any more painful than it has to
Now let's look at Slide CS-14, so we'll
take nine and eight, so CS-14, and now I look at
myocardial infarction, and it's 16 to 4. And so
when you put it together, you know, you see that
the really serious events, the bad things that can
happen to that patient I'm seeing in
look a lot worse on ximelagatran than warfarin.
And so one has to ask the question: Does it really
look as good as it looks?
And so what are your thoughts about this?
I mean, MI is as bad an outcome as PE, isn't it?
DR. SHETH: Yes, it is. In considering
those numbers, I won't dispute how--the numbers
that we just looked at, they are higher in the
ximelagatran group compared to the warfarin group
in the orthopedic surgery population. The only
comment I'd make is that, unfortunately--those are
really small numbers, and the question is: Is this
a really--a true difference? And I would
anticipate that if it was a true effect that we
would really see a significant effect in the
long-term group just because it's so much larger.
We also have another study that we started
to do in extended prophylaxis in orthopedic
surgery, so we'll be able to collect more data in
that study as well. But, again, the numbers are
small so it's hard to know if this is a true
difference or not.
DR. NISSEN: But, of course, the
difference in the long-term studies is that this is
one where you get the short-term administration,
then you withdraw the drug, and so it speaks more
to this question of an acute rebound sort of
phenomenon. I mean, I hope you can appreciate why
it's something that really struck many of us on the
committee as being a problem.
DR. BORER: It's also a potentially
remediable problem, so it's important that you
should know about it.
Bill, and then Beverly.
DR. HIATT: Yes, just to follow up on
that, it does seem like the surgical population may
not be the same as the long-term treatment
population, and the concept of risk
occurring--excess risk occurring in that population
is very real.
Then the other question I have is, turning
to the SPORTIF IV data, you didn't present that in
any of your safety data. Is that correct?
DR. SHETH: The SPORTIF II and IV data are
actually pooled in the atrial fibrillation pool
that we performed. So it included that Phase II
DR. HIATT: If you look at page 97 of the
briefing document, there are several phases to
SPORTIF IV, and I count a total of 17 deaths on
treatment versus warfarin is four. So you're
saying those deaths are included in the overall
safety data you presented?
DR. SHETH: They are included, but I'll
just point out that there are about 2 to 3 times
more patients on--3 times more patients on
ximelagatran than on warfarin in SPORTIF IV. So
they're not balanced groups. The denominators are
DR. HIATT: Correct.
DR. SHETH: But those deaths are included
in the atrial fib pool and consequently in the
long-term exposure pool.
DR. HIATT: Okay.
DR. BORER: Beverly, and then Dr. Sjogren.
DR. LORELL: To follow up on this concept
of potential rebound--
DR. SHETH: Can you speak louder?
DR. LORELL: Yes, I can. To follow up on
the issues that were raised about potential rebound
in the post-surgical population, can you enlighten
us as to how investigators were instructed to use
or no instructions on aspirin? Was aspirin
deliberately not used in that surgical population?
And then were there any instructions at the
termination of treatment?
DR. SHETH: Let me ask Dr. Berkowitz, who
was the physician for those studies, to describe
the use of aspirin instructions for the surgical
DR. BERKOWITZ: Scott Berkowitz,
AstraZeneca. I didn't get the second part. The
first part was that aspirin was precluded, kept to
a minimum, and patients weren't to be on it
DR. LORELL: So I think the second part,
was there a strategy in that trial when the study
drug was stopped about reinstatement of
patients who had risk factors? You know, the point
that Dr. Borer made, this is a group with rich risk
DR. BERKOWITZ: I'm sorry. I think I got
all your question. The studies were designed to
leave to the discretion of the investigators to put
the patients back on the medicine, so we did not
prespecify how to do that.
DR. LORELL: Okay. And related to that,
have you done any studies after withdrawal of the
drug to look at what happens to platelet function?
DR. BERKOWITZ: In our clinical trials for
VTE and orthopedic surgery and I believe in the
atrial fibrillation trials, we did not do any
DR. SHETH: I can mention we actually
looked and did an analysis of patients both on
ximelagatran, on aspirin and off aspirin, for
events in the atrial fibrillation pool. If you're
interested, we can show that if that would be
helpful. And this is not exactly the same as the
patients who discontinued after
But if you're concerned about any increased
beneficial effect--let's see. Actually, what you
see is that there is an incremental benefit in
patients who are on aspirin, but you see that same
benefit on warfarin, and you don't see a difference
of the effect between the two anticoagulants when
aspirin is added.
DR. BORER: The question that Beverly is
asking, though, is what about after you've stopped
the ximelagatran and the warfarin. In that period,
were people still on aspirin or were they not? And
did the fact that they were or weren't have any
impact on the post-treatment events?
DR. SHETH: We didn't make specific
recommendations after the trial. They were to go
on their regular medications per their physician.
DR. BORER: Okay. Dr. Sjogren, then Alan,
DR. SJOGREN: My question pertains to the
potential hepatic toxicity, and I have a couple of
questions. One is you are proposing to follow up
patients with ALTs, and then if they go
times the upper limit of normal, to follow up a
little more closely and eventually discontinue the
drug. I'd like to know what kind of information do
you have in the patients that you followed up that
developed the ALT abnormality to back up that kind
of recommendation. That's one question.
The second question is: Do you have any
information on patients with chronic liver disease
that are treated with this medication? What
happens to them?
And one request. Do you have slides of
the liver biopsy that was done that we can look at?
DR. BORER: Before you begin to answer,
let me just state a rule here. We're not asking
you to tell us your algorithm for following
patients. Dr. Sjogren is just asking about the
data that might be used to inform the development
of such an algorithm and then the issue of the
chronic use and the slides.
DR. SHETH: Okay. Let me answer the
latter two questions first, and I'm going to have
to ask for a clarification on that first
We do not have a slide of the hepatic
biopsy right now. The chronic disease, because we
identified early in the Phase II trial, SPORTIF II,
that there was this asymptomatic transaminase
increase, we actually excluded patients who had
known hepatic disease from the trials, as well as
patients who had an ALT above 2 times the upper
limit of normal. So that to the best of our
knowledge, patients who--with the exception of the
reactivation hepatitis B, should not have, in fact,
been enrolled in the trial, and we would, in fact,
propose a contraindication for those patients. So
we don't have data to understand the safety in that
In terms of follow-up, are you asking
me--you want to know what did we do to follow up
all patients who had an elevation or what their